Dr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\\n\\n
Seeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\\n\\n
Over these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\\n\\n
We are excited about the present, and we look forward to sharing many more successes in the future.
\\n\\n
Thank you all for being part of the journey. 5,000 times thank you!
\\n\\n
Now with 5,000 titles available Open Access, which one will you read next?
Preparation of Space Experiments edited by international leading expert Dr. Vladimir Pletser, Director of Space Training Operations at Blue Abyss is the 5,000th Open Access book published by IntechOpen and our milestone publication!
\n\n
"This book presents some of the current trends in space microgravity research. The eleven chapters introduce various facets of space research in physical sciences, human physiology and technology developed using the microgravity environment not only to improve our fundamental understanding in these domains but also to adapt this new knowledge for application on earth." says the editor. Listen what else Dr. Pletser has to say...
\n\n\n\n
Dr. Pletser’s experience includes 30 years of working with the European Space Agency as a Senior Physicist/Engineer and coordinating their parabolic flight campaigns, and he is the Guinness World Record holder for the most number of aircraft flown (12) in parabolas, personally logging more than 7,300 parabolas.
\n\n
Seeing the 5,000th book published makes us at the same time proud, happy, humble, and grateful. This is a great opportunity to stop and celebrate what we have done so far, but is also an opportunity to engage even more, grow, and succeed. It wouldn't be possible to get here without the synergy of team members’ hard work and authors and editors who devote time and their expertise into Open Access book publishing with us.
\n\n
Over these years, we have gone from pioneering the scientific Open Access book publishing field to being the world’s largest Open Access book publisher. Nonetheless, our vision has remained the same: to meet the challenges of making relevant knowledge available to the worldwide community under the Open Access model.
\n\n
We are excited about the present, and we look forward to sharing many more successes in the future.
\n\n
Thank you all for being part of the journey. 5,000 times thank you!
\n\n
Now with 5,000 titles available Open Access, which one will you read next?
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"84",leadTitle:null,fullTitle:"Theory and Applications of CT Imaging and Analysis",title:"Theory and Applications of CT Imaging and Analysis",subtitle:null,reviewType:"peer-reviewed",abstract:"The x-ray computed tomography (CT) is well known as a useful imaging method and thus CT images have continuingly been used for many applications, especially in medical fields. This book discloses recent advances and new ideas in theories and applications for CT imaging and its analysis.\nThe 16 chapters selected in this book cover not only the major topics of CT imaging and analysis in medical fields, but also some advanced applications for forensic and industrial purposes. These chapters propose state-of-the-art approaches and cutting-edge research results.",isbn:null,printIsbn:"978-953-307-234-0",pdfIsbn:"978-953-51-6427-2",doi:"10.5772/616",price:139,priceEur:155,priceUsd:179,slug:"theory-and-applications-of-ct-imaging-and-analysis",numberOfPages:302,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"1c2713601b49dbbc072998268cdc16eb",bookSignature:"Noriyasu Homma",publishedDate:"April 4th 2011",coverURL:"https://cdn.intechopen.com/books/images_new/84.jpg",numberOfDownloads:53078,numberOfWosCitations:30,numberOfCrossrefCitations:18,numberOfCrossrefCitationsByBook:1,numberOfDimensionsCitations:35,numberOfDimensionsCitationsByBook:1,hasAltmetrics:0,numberOfTotalCitations:83,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 18th 2010",dateEndSecondStepPublish:"June 15th 2010",dateEndThirdStepPublish:"September 20th 2010",dateEndFourthStepPublish:"November 19th 2010",dateEndFifthStepPublish:"February 2nd 2011",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"3411",title:"Prof.",name:"Noriyasu",middleName:null,surname:"Homma",slug:"noriyasu-homma",fullName:"Noriyasu Homma",profilePictureURL:"https://mts.intechopen.com/storage/users/3411/images/1650_n.jpg",biography:"Dr. Noriyasu Homma received a BA, MA, and PhD in electrical and communication engineering from Tohoku University, Japan, in 1990, 1992, and 1995, respectively. \nFrom 1995 to 1998, he was a lecturer at the Tohoku University, Japan. He is currently an associate professor of the Cyberscience Center at the Tohoku University. From 2000 to 2001, he was a visiting professor at the Intelligent Systems Research Laboratory, University of Saskatchewan, Canada. His current research interests include neural networks, complex and chaotic systems, soft-computing, cognitive sciences, medical systems and brain sciences. 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1. Introduction
Mitochondria are dynamic subcellular organelles present in virtually all eukaryotic cells with numerous functions. The most important of these functions is production of ATP; however they play an important role in various metabolic and developmental processes such as calcium homeostasis, apoptosis and programmed cell death, just to mention some. Mitochondria produce ATP by means of the mitochondrial respiratory chain (MRC) and oxidative phosphorylation (OXPHOS) system, a series of five enzyme complexes embedded in the inner mitochondrial membrane. Mitochondrial disorders most often refer to the dysfunction of OXPHOS system leading to deficiency in the ATP production. They are a group of genetically and phenotypically heterogeneous disorders with an incidence estimated to be between 1:5,000 and 1:10,000 live births [1].
MRC is the result of the interplay of two physically and functionally separated genomes, the nuclear DNA (nDNA) and mitochondrial DNA (mtDNA). Thirteen of the key structural polypeptides that constitute the multimeric subunits of the respiratory chain complexes are mtDNA encoded, in addition two ribosomal RNA (rRNA) and 22 transfer RNA (tRNA) that are required for initiating translation and protein synthesis [2]. Approximately 90 of the remaining proteins that make up the respiratory chain complexes are encoded by nDNA. Therefore, although human mtDNA encodes the basic machinery for protein synthesis, it depends entirely on the nucleus for the provision of enzymes for replication, repair, transcription, and translation. This dependency lies at the heart of several newly recognized human diseases that are characterized by secondary abnormalities of mtDNA.
The crosstalk between the two genomes is crucial for the cellular regulation of mtDNA integrity and copy number and correct mitochondrial protein production therefore mutations in genes involved in mitochondrial replication and maintenance can disrupt the integrity of the mitochondrial genome, causing inter-genomic communication disorders. Multiple deletions, depletion of mtDNA or a combination of both phenomena (qualitative/quantitative lesions) in critical tissues, are the hallmarks of these disorders.
The focus of this chapter is to review the clinical and molecular etiologies of nuclear defects involved in mtDNA stability and in mitochondrial protein synthesis. The overview done here will hopefully provide insights towards best diagnostic strategies of mitochondrial cross–talk disorders, being useful for clinicians when facing similar cases. Additionally we will present a diagnostic algorithm for these diseases based on our knowledge.
2. Clinical manifestations of disorders affecting mtDNA integrity
Maintenance of mtDNA is controlled by an intricate homeostatic network, whose effectors are the various components of the mitochondrial replicosome and the many enzymes and carrier proteins that provide the mitochondrion with a balance supply of deoxyribonucleotides (Figure 1). As all of the factors are nDNA encoded, it is not surprising that mutations in genes involved in mitochondrial replication and maintenance can disrupt the integrity of the ‘‘tiny’’ mitochondrial genome [3] leading to multiple deletions or depletion [4]. The mitonuclear crosstalk has gained increased relevance in the past years and since then many genes have been identified as being involved in these diseases.
In the following section we will briefly review the clinical manifestations of both these group of disorders.
2.1. mtDNA multiple deletion syndromes
Mitochondrial diseases associated with the presence of multiple deletions of mtDNA are mostly autosomal dominant, occurring most often in adulthood. The size and terminals deletions are variable from one individual to another within the same family.
The main clinical manifestations associated with multiple deletions are:
PEO (autosomal dominant or recessive Progressive External Ophthalmoplegia). The most common clinical features include adult-onset of weakness of the external eye muscles, bilateral ptosis, proximal muscle weakness wasting and exercise intolerance. Additional symptoms are variable, and may include cataracts, hearing loss, sensory axonal neuropathy, ataxia, depression, hypogonadism, and Parkinsonism. Less common features include mitral valve prolapse, cardiomyopathy, and gastrointestinal dysmotility. Both autosomal dominant and autosomal recessive inheritance can occur; autosomal recessive inheritance is usually more severe [5,6]. The multiple deletions associated with PEO are exclusively found in muscle tissues of patients.
SANDO (Sensory Ataxic Neuropathy, Dysarthria and Ophthalmoparesis) is an autosomal recessive systemic disorder characterized mainly by adult onset of sensory ataxic neuropathy, dysarthria, and ophthalmoparesis. The phenotype varies widely, even within the same family, and can include myopathy, seizures, and hearing loss, but the common clinical feature appears to be sensory ataxia [7].
Figure 1.
Schematic overview of the mitochondrion and the mitochondrial disease genes involved in intergenomic communication disorders. Zooming in on the mitochondrion allows identification of genes (namely, POLG and C10orf2- Twinkle) thought to be involved in replication of mitochondrial DNA (mtDNA); those assumed to affect the metabolism of the mitochondrial deoxynucleotide (dNTP) pool (via progressive phosphorylations of deoxythymidine, deoxycytidine, deoxytadenine, and deoxiguanosine); and those belonging to the tricarboxylic acid cycle and affecting the respiratory chain complexes (OXPHOS). Moreover, the supposed role of genes involved in the complex machinery of mitochondrial protein synthesis (including the aminoacyl-tRNA synthetases) is illustrated. This figure was kindly provided by Prof. Filippo M. Santorelli.
MNGIE (Mitochondrial NeuroGastroIntestinal Encephalomyopathy), an autosomal recessive disorder clinically characterized by onset between the second and fifth decades of life, PEO, gastrointestinal dysmotility (often pseudo-obstruction), cachexia, diffuse leukoencephalopathy, peripheral neuropathy and early death. Mitochondrial DNA abnormalities can include depletion, multiple deletions, and point mutations [8].
SCAE (SpinoCerebellar Ataxia – Epilepsy syndrome) disorder similar to SANDO but with a higher frequency of migraine headaches and seizures [9].
2.2. mtDNA depletion syndromes
Quantitative alterations are characterized by depletion of mtDNA. Mitochondrial DNA depletion syndrome (MDS) comprises a heterogeneous group of autosomal recessive disorders, all having the same molecular end result, low mtDNA amount in specific tissues. MDS are a group of rare and devastating diseases that manifest typically, although not exclusively, soon after birth, determining early death usually in infancy or early childhood. MDS differs from other respiratory chain disorders, as most often it may manifest solely in a specific organ (most commonly muscle or liver) [10]. However, it may occur that multiple organs, including heart, brain, and kidney are affected [11]. An extensive review on MDS was recently published [12].
Three major clinical categories can be recognized however, the clinical phenotypes are heterogeneous, overlapping and ever expanding [10,13]:
Hepatocerebral MDS is most probably the most common variant of MDS; Onset of symptoms is between birth and 6 months; death usually occurs within one year of age. The most common symptoms and signs include persistent vomiting, failure to thrive, hypotonia and hypoglycemia associated with progressive neurological symptoms. Histological changes on liver biopsy include fatty degeneration, bile duct proliferation, fibrosis, and collapse of lobular architecture. Reduced COX histochemistry and combined deficiency of mtDNA encoded MRC complexes were found in the liver of a few patients.
A peculiar form of hepatocerebral MDS is Alpers-Huttenlocher syndrome, an early onset, fatal disease, characterized by hepatic failure, intractable seizures, evolving into epilepsia partialis continua, and global neurological deterioration. The liver dysfunction is usually progressive as well, evolving from microvesicular staetosis with bile duct proliferation into cirrhosis and chronic liver failure.
Myopathic MDS typically onset of symptoms usually occur in the first year of life with feeding difficulty, failure to thrive, hypotonia, muscle weakness and occasionally PEO. Death is usually due to pulmonary insufficiency and infections, but some patients survive into their teens [14,15]. Muscle biopsy may show proliferation of mitochondria, which can increase with age, and patchy or diffuse COX deficiency. Biochemical defects of all mtDNA-related respiratory chain complexes are always present in muscle mitochondria. Serum CK levels may be variably elevated [4].
Encephalomyopathic MDS is characterized by infantile onset of hypotonia with severe psychomotor retardation, high lactate in blood, progressive neurologic deterioration, a hyperkinetic-dystonic movement disorder, external ophthalmoplegia, deafness, generalized seizures and variable renal tubular dysfunction. Brain MRI was suggestive of Leigh syndrome [11].
3. Molecular etiologies of disorders affecting mtDNA integrity
In the next sections we will mention the genes identified so far, to be responsible with these disorders. Table 1 summarizes the mutations described and the associated phenotypes.
Table 1.
Mutations types described in genes involved in mtDNA integrity and mitochondrial translation and associated clinical phenotype (M/N- missense/nonsense; Sp- splicing; Sd- small deletions; Si- small insertions; Sid- small inddels; Gd- gross deletions; Gi- gross insertions; Gr- gross rearrangements) - source HGMD Professional database www.hgmd.cf.ac.uk/.
3.1. Genes involved in mitochondrial replisome
3.1.1. POLG
Human mitochondria contain a single DNA polymerase, Polymerase gamma (POLγ), nuclear encoded and solely responsible for mtDNA replication and repair in mitochondria. POLγ is composed of a catalytic subunit, POLγA, which possesses both polymerase and proofreading exonuclease activities and an accessory subunit, POLγB, which increases enzyme processivity [16]. The POLγ holoenzyme functions in conjunction with the mitochondrial DNA helicase and the mitochondrial single-stranded DNA- binding protein to form the minimal replication apparatus [17]. It was generally accepted that mutations within the mtDNA were the major cause of mitochondrial diseases; however this view is changing as several of these have been linked to ineffective mtDNA replication by POLγ.
Mutations affecting the catalytic subunit POLγA, encoded by the nuclear gene POLG are a major cause of mitochondrial disease, being highly heterogeneous – PEO, Parkinsonism, AHS, MNGIE, SANDO and SCAE- and usually is associated with multiple mtDNA deletions [18]. POLG mutations have been shown to be associated with all types of inheritance. The unique features of mitochondrial physiology are in part responsible for this variability but POLG structure and function add to the riddle of how one gene product can demonstrate autosomal recessive and autosomal dominant transmission. POLγA is a key player in mtDNA maintenance that is absolutely necessary for mtDNA replication from an early stage in embryogenesis [19]
In adPEO due to POLG mutations (most frequent), prominent features are severe dysphagia and dysphonia, and, occasionally, a movement disorder including Parkinsonism, cerebellar dysfunction, and chorea. Recessive mutations of POLG are responsible for sporadic and arPEO, as well as the syndromes referred above. Mutations in this gene can be also associated to the hepatocerebral form of MDS, namely AHS [18].
The POLG gene is located at chromosome 15, comprises 23 exons spanning 18.55 Kb. The gene was identified in 1996 [20] but only in 2001 the first pathogenic mutation was described. Since then more than 150 mutations have been reported and POLG gene is considered a hot-spot for mutations in mitochondrial diseases [21].
3.1.2. POLG2
MtDNA is replicated by DNA polymerase gamma, which is composed of a 140-kD catalytic subunit (encoded by POLG) and a 55-kD accessory subunit (POLG2). The accessory subunit increases enzyme processivity therefore it is not surprising that failure in this processivity leads to the accumulation of mtDNA deletions.
The POLG2 gene is located at chromosome 17, comprises 8 exons spanning 19.28 Kb. In 2006 the first pathogenic mutation was described as being a cause of adPEO [22]. Since then, 10 mutations in POLG2 have been reported.
3.1.3. C10orf2 (Twinkle)
The mitochondrial helicase/primase encoded by C10orf2 gene is also responsible for the adPEO [23]. Mutations in C10orf2 may be of variable severity, being associated with clinical presentations ranging from late-onset ‘‘pure’’ PEO, to PEO complicated by proximal limb and facial muscle weakness, dysphagia and dysphonia, mild ataxia, and peripheral neuropathy. Recessive C10orf2 mutations were also described in patients with hepatocerebral form of MDS [24].
The C10orf2 gene is located at chromosome 10; it comprises 5 exons spanning 6.38 kb. The first pathogenic mutation was reported in 2001 [23] to be associated with PEO and since then 45 pathogenic mutations have been reported.
3.2. Genes involved in the synthesis and supply of nucleotide pools
3.2.1. SLC25A4
This gene, coding for the muscle-heart-specific mitochondrial adenine nucleotide translocator (ANT) is a member of the mitochondrial carrier subfamily of solute carrier protein genes [25]. ANT is the most abundant mitochondrial protein and in its functional state, it is a homodimer of 30-kD subunits embedded asymmetrically in the inner mitochondrial membrane. The dimer forms a gated pore through which ADP is moved from the matrix into the cytoplasm. There are three recognized isoforms of this protein.
Mutations in this gene have been shown to be responsible for the adPEO and have been also associated with a relatively mild, slow progressive myopathy, with little or no extramuscular symptoms.
The SLC25A4 gene was identified in 2000 [25], it is located at chromosome 4, comprises 4 exons spanning 4.04 Kb. The first pathogenic mutations were described in 2000 and since then only seven mutations have been reported (most of them associated with PEO).
3.2.2. SLC25A3
The SLC25A3 gene codes for a mitochondrial phosphate carrier. A defect in this mitochondrial phosphate carrier has been described in two children with hypertrophic cardiomyopathy, muscular hypotonia, severe growth retardation and death in the first year of life [26].
The gene is located at chromosome 12, comprises 7 exons spanning 8.37 Kb. The first pathogenic mutations were described in 2007 [26] and since then only one more mutation has been reported.
3.2.3. Tymp (ECGF1)
The Tymp gene, responsible for MNGIE (Mitochondrial NeuroGastroIntestinal Encephalomyopathy), encodes the enzyme thymidine phosphorylase (TP), which is involved in pyrimidines catabolism. Defects of TP result in systemic accumulation of thymidine and deoxyuridine, which leads to deoxynucleotide pool imbalance and mtDNA instability, resulting in the presence of multiple deletions and partial depletion of muscle mtDNA [27].
The Tymp gene is located at chromosome 22 it comprises 10 exons spanning 4.3 kb. The first pathogenic mutations were described in 1999 [27] and since then 65 mutations have been described as being associated with MNGIE.
3.2.4. TK2
Thymidine kinase (TK2) is an intramitochondrial pyrimidine nucleoside kinase that phosphorylates deoxynucleotides (dNTPs), such as: deoxythymidine, deoxycytidine, and deoxyuridine, thereby participating in the salvage pathway of deoxynucleotide synthesis in the mitochondria [28]. Mitochondrial dNTPs pools arise either through active transport of cytosolic dNTP or through salvage pathways. Both pathways are essential for the replication of mtDNA, since the mitochondrion is unable to synthesize dNTPs de novo. Mutations in the TK2 gene on chromosome 16q22 affect primarily muscle tissue, with little or no effect on the liver, brain, heart, or skin. The typical manifestation of TK2 mutations is a severe, rapidly progressing myopathy of infantile or childhood onset. The disease course is rapidly progressive, leading to respiratory failure and death in months or years, but milder phenotypes with slower progression and longer survival have been reported [10]. Since the first mutation was described in 2001 [29], approximately 25 different pathogenic mutations in TK2 have been published so far, either as recessive homozygous or compound heterozygous mutations, and phenotypes may be explained by variable degrees of residual activity of the mutant enzymes.
3.2.5. DGUOK
Deoxyguanosine kinase is a 2-deoxyribonucleoside enzyme that catalyzes the first step of the mitochondrial deoxypurine salvage pathway, the phosphorylation of purine deoxyribonucleosides into the corresponding nucleotides deoxyguanosine and deoxyadenosine necessary for the maintenance of mitochondrial dNTPs pools [11,30]. The typical phenotype of mutations in the DGUOK gene, on chromosome 2p13, is characterized by neonatal onset of progressive liver disease and feeding difficulties, usually with neurological dysfunction (hypotonia, nystagmus, and psychomotor retardation), by the age of 3 months. Peripheral neuropathy and renal tubulopathy have occasionally been reported [31]. Depletion of mtDNA has been documented only in the liver and results in combined respiratory chain deficiencies in the liver, whereas the amount of mtDNA is usually normal in muscle and fibroblasts. Histological analyses of the liver biopsy show variable findings, typically microvacuolar steatosis, cholestasis, fibrosis, and cirrhosis. In most cases, there is a rapidly progressive liver disease and neurological deterioration, with death occurring by the age of 12 months or shortly thereafter [32]. The first pathogenic mutations was reported in 2001 [33], since then more than 80 affected patients from approximately 50 families have been reported, and over 40 different DGUOK mutations have been identified [10]. The infantile hepatocerebral form of MDS is the almost invariable clinical presentation. Genotype-phenotype correlation studies show that patients who harbor null mutations usually have early onset liver failure and significant neurological disease, including hypotonia, nystagmus, and psychomotor retardation, and death before two years of age. Patients carrying missense mutations usually have isolated liver disease, a better prognosis, and longer survival.
3.2.6. RRM2B
The RRM2B gene on chromosome 8q23 encodes the small subunit of p53-inducible ribonucleotide reductase, a heterotetrameric enzyme responsible for de novo conversion of ribonucleoside diphosphates into the corresponding deoxyribonucleoside diphosphates that are crucial for DNA synthesis [34]. The enzyme is the main regulator of the nucleotide pools in the cytoplasm, and its small subunit is expressed in postmitotic cells, where it probably has a key function in maintaining the mitochondrial dNTPs pools for mtDNA synthesis. Mutations in RRM2B usually result in hypotonia, lactic acidosis, failure to thrive, and tubulopathy in the first months of life. The disease has a rapid progression and leads to death in a few months. The associated complex phenotype suggests that the consequences of a defective mitochondrial dNTPs pools can vary dramatically depending on the residual amount of the functional enzyme. Recently, it has been shown that inactivating mutations in RRM2B also cause severe neonatal or infantile forms of mtDNA depletion, with profound reduction of mtDNA copy numbers in skeletal muscle [34]. The first pathogenic mutation was reported in 2007 [34] and since then 26 mutations have been described.
3.2.7. MPV17
The MPV17 gene is located on chromosome 2p23-p21 and encodes a mitochondrial inner membrane protein of unknown function recently recognized as responsible for mtDNA depletion. The clinical presentation is that of severe liver failure, hypoglycemia, growth retardation, neurological symptoms, and multiple brain lesions during the first year of life [35]. Marked mtDNA depletion in the liver is the molecular hallmark associated with multiple defects of respiratory chain complexes. Normal or mildly reduced levels of both mtDNA content and respiratory chain enzyme activities were also found in muscle [36]. Histological analyses of the liver have revealed swollen granular hepatocytes, microvesicular steatosis, and focal pericellular and periportal fibrosis. Since the first mutation was described in 2006 [37], about 15 different mutations have been reported in infantile-onset hepatocerebral syndrome and in Navajo neurohepatopathy, which is an autosomal recessive multisystem disorder found in the Navajo of the southwestern United States [30]. Three main subtypes are to be considered: infantile-onset (before 6 months) and childhood-onset (before 5 years) forms with hypoglycemic episodes and severe progressive liver dysfunction requiring liver transplant, and a ‘classic’’ form with moderate hepatopathy and progressive sensorimotor axonal neuropathy. The three forms are also associated with variable degrees of demyelination in both the central and the peripheral nervous system.
3.2.8. SUCLA2 and SUCLG1
Succinyl CoA synthase is a mitochondrial matrix enzyme that catalyzes the reversible synthesis of succinate and ATP or GTP from succinyl-CoA and ADP in the tricarboxylic acid cycle. This enzyme is made up of two subunits, a and b, encoded by SUCLG1 on chromosome 2p11 and SUCLA2 on 13q12, respectively. Mutations in SUCLA2 and SUCLG1 cause an encephalomyopathic form of infantile mtDNA depletion syndrome, but SUCLG1 can also cause a very severe disorder with antenatal dysmorphisms, neonatal metabolic crisis, and early death, probably depending on the lower residual amount of the protein [38,39]. A useful diagnostic clue in Succinyl CoA synthase disorders of succinyl CoA synthase is a ‘‘mildly’’ elevated urinary methylmalonic acid, which is detected in all patients, and presence of tricarboxylic acid cycle intermediates (methylcitrate, lactate, carnitine esters, 3-hydroxyisovalericacid) in most cases. Some patients die as infants (sudden infant death syndrome), but some of them have a longer survival. The clinical features of patients with mutations in these genes include early childhood hypotonia, developmental delay, and almost invariably, progressive dystonia and sensorineural deafness. SUCLA2 and SUCLG1 mutations seem to disrupt an association between succinyl CoA synthase and mitochondrial nucleoside diphosphate kinase, resulting in an unbalanced mitochondrial dNTP pool and eventually, mtDNA depletion in muscle. The first pathogenic mutations were reported in 2005 [40] and 2007 [41] in SUCLA2 and SUCLG1, respectively and since then few mutations have been described.
3.3. Genes involved in mitochondrial translation
Mendelian diseases characterized by defective mitochondrial protein synthesis and combined respiratory chain defects have also been described in infants and are associated with mutations in nuclear genes that encode components of the translational machinery, such as those encoding elongation factors, aminoacyl-tRNA synthetases, or even mtDNA encoded tRNA [12]. Mitochondria contain a separate protein-synthesis machinery to produce the polypeptides encoded in mtDNA, and many mtDNA disease mutations affect this machinery. This group of disorders is highly heterogeneous and usually shares a combined disorder of respiratory chain complexes.
3.3.1. Genes involved in mitochondrial translation factors
3.1.1.1. PUS1\n\t\t\t\t\t
The Pseudouridine synthase 1 (PUS1) gene on chromosome 12q24 encodes an enzyme that converts uridine into pseudouridine at several cytoplasmic and mitochondrial tRNA positions and thereby improves translation efficiency in the cytosol as well as the mitochondrion. Thus, PUS1 is not part of the translation machinery, but it is required for protein synthesis because of its function in posttranscriptional modification of tRNA. Mutations in PUS1 are responsible for the rare myopathy, lactic acidosis, sideroblastic anemia syndrome and sometimes include mental retardation. The first pathogenic mutation was reported in 2004 [42] and since then few mutations have been described.
3.1.1.2. TRMU
The TRMU gene on chromosome 22q13 encodes an evolutionarily conserved protein involved in mitochondrial tRNA modification and is important for mitochondrial translation. Defects in tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase (TRMU), a mitochondria specific enzyme that is required for the 2-thiolation on the wobble position of the tRNA anticodon, result in reduced steady-state levels of 3 tRNA (tRNALys, tRNAGln, and tRNAGlu) and consequently, impaired mitochondrial protein synthesis [43,44]. Recently, mutations in TRMU were detected in patients with acute liver failure in infancy [44].
3.1.1.3. LRPPRC
The LRPPRC gene is located on chromosome 2p21. Leucine-rich PPR-motif containing protein has been suggested to function together with heterogeneous nuclear ribonucleoprotein K and RNA polymerase in coupling the mitochondrial transcription and translation machineries [45]. Mutations in LRPPRC lead to the French-Canadian subtype of Leigh syndrome, associated with a profound deficiency of complex IV of the OXPHOS system [46]. Patients exhibit neonatal or infantile onset hypotonia and psychomotor delay, and bilateral hyperluciencies of basal ganglia, like other more common forms of Leigh syndrome. The first pathogenic mutation was reported in 2003 [46] and since then one more mutation has been described.
3.1.1.4. TACO1
TACO1 represents the first specific mammalian mitochondrial translational activator, opening the possibility to a new class of proteins controlling efficiency of mitochondrial translation. Mutations in TACO1, located on chromosome 17q.6, are responsible for a relatively late-onset Leigh syndrome (onset range 4-13 years) characterized by short stature, mental retardation with autistic-like features, and a slowly progressive array of motor symptoms related mainly to basal ganglia involvement [47,48]. Only one mutation was described to date [47].
3.1.1.5. TUFM, TSFM and GFM1
Another important player during mitochondrial protein biosynthesis is the group of elongation factors. The mitochondrial EF-Tu forms a ternary complex with tRNA and GTP and promotes the binding of tRNA to the ribosome. A few patients have been described as having mutations in genes encoding components of the mitochondrial translation elongation machinery, including elongation factor EF-Tu (TUFM), EF-Ts (TSFM) and EFG1 (GFM1). These patients have severe disease, presenting neonatal lactic acidosis and neurological impairment resembling Leigh syndrome, leading to early fatality. The first pathogenic mutations in these genes were reported recently [49,50,51] and since then few mutations have been described.
3.1.1.6. MRPS16 and MRPS22\n\t\t\t\t\t
Of all 81 human mitochondrial ribosomal proteins (MRPs), mutations have been found in only two, MRPS16 and MRPS22 [52,53]. Both defects resulted in a marked decrease in the 12S rRNA transcript level, probably caused by impaired assembly of the mitoribosomal small subunit, generating unincorporated and unstable 12S rRNA. Indeed, lack of MRPs results in the failure to assemble parts of small subunits of the mitoribosome, and subsequent degradation of its components [54]. Clinical manifestations include agenesis of the corpus callosum, dysmorphism, hypertrophic cardiomyopathy, and fatal neonatal lactic acidosis. The first pathogenic mutations were reported in 2004 [52] and in 2007 [53], and since then few mutations have been described.
3.3.2. Genes involved in mitochondrial aminoacyl tRNA synthetases
3.3.2.1. RARS2, DARS2, and YARS2\n\t\t\t\t\t
To guarantee fidelity in translation, it is important to attach the right amino acid to the tRNA and to ensure that the tRNA recognizes, through its anticodon, the correct codon in the ribosomal A-site. Incorporation of an incorrect amino acid into the nascent polypeptide could cause misfolding and production of defective or dominant interfering proteins. Amino acids are attached to tRNA by amino-acyl-tRNA synthetases, each of which is specific for a single amino acid. However, as there can be several codons and several different tRNA for a single amino acid, an amino-acyl-tRNA synthetase can ‘‘charge’’ several different tRNA. If this function is defective, certain codons will become ambiguous, resulting in the synthesis of misfolded proteins, which could aggregate to form inclusions and induce further protein misfolding. Mutations in the RARS2 and DARS2 were recently described [55,56,57] and are associated with severe encephalopathy with pontocerebellar hypoplasia and leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation, respectively, with most patients showing onset between 2-15 years of age [56]. Very recently, mutations in the gene encoding the mitochondrial YARS2 have been associated with a clinical condition characterized by myopathy, lactic acidosis, and sideroblastic anemia [54].
4. Diagnostic approaches for intergenomic communication disorders
Suspicion of intergenomic communication disorders arising from clinical presentation may range from well defined syndromes to unspecific multisystemic phenotype, where neurological involvement is usually present.
Establishing a specific diagnosis in a patient with suspected mendelian disease is a challenging task that requires the integration of clinical assessments, family history, biochemical testing and histopathological examination. It is important to obtain the appropriate biochemical and/or clinical information before starting any molecular investigations so that molecular diagnosis can be successfully.
Biochemical determination of mitochondrial respiratory chain complexes is important for delineating the molecular approach in particular in patients without a specific neurological syndrome. As mtDNA encodes for subunits of respiratory chain complexes I, III, IV and the ATP-synthase, mtDNA depletion causes a combined respiratory chain deficiency of all complexes, except complex II. Biochemical analysis of the muscle respiratory chain enzyme activities may, however, be normal, if skeletal muscle is not among the affected tissues, e.g., in MDS of the brain or liver. Southern analysis or quantitative real-time polymerase chain reaction are two methods that simultaneously detects mtDNA deletion(s) and quantify total mtDNA content. In both approaches, mtDNA amount is compared to a specific nuclear reference gene. A prerequisite for correct interpretation of mtDNA amount is to consider the dynamic nature of mtDNA amount in different ages and tissues, and therefore to establish carefully age-matched control materials [58]. A reduction in mtDNA copy number to 60-65% of age-matched controls has been established for an empirical cut-off level for MDS diagnosis, but especially in children, the reduction may be severe (80-90%). Biochemical data, such as lactate, pyruvate, alanine, organic acid profiles as well as neuroimaging findings are also important clues for the diagnosis of these disorders. Some diagnostic clues exist for specific gene defects: serum creatine kinase (CK) is elevated in TK2 defects, serum thymidine in TYMP defects and urine methylmalonic acid and methylcitrate in SUCLA2 and SUCLG1 defects [10].
The POLG gene seems to be the most frequently mutated nuclear gene in cases of mitochondrial disease therefore in cases of normal mtDNA testing and clinical signs such as nonspecific hypotonia, developmental delay, epilepsy and progressive liver disease POLG gene investigation should be considered. Valproate-induced liver toxicity in POLG and C10orf2-MDS emphasizes the importance of diagnosing these patients, who usually suffer from severe treatment-resistant epilepsy [59]. We suggest POLG analysis before valproate treatment for such children and adolescents, whose first epileptic attack develops to a status epilepticus of unknown cause.
Based on our practice, we present a testing algorithm for establishing an accurate diagnosis for these diseases (Figure 2).
5. Therapeutic considerations
The management of mitochondrial disease is largely supportive as no curative therapy is available. Palliative/supportive treatment with vitamins, cofactors and respiratory substrates have been used, but with poor efficacy. In the last years several approaches have been tried and the enhancement of mitochondrial biogenesis has emerged as an exciting therapeutic possibility. The enhancement of mitochondrial biogenesis might restore mitochondrial function in a variety of other contexts.
Figure 2.
Diagnostic algorithm for intergenomic communication disorders, based on clinical and biochemical information.
What has been noticed is that for every case there is a different strategy. For example liver transplantation may be beneficial to patients with hepatopathy caused by DGUOK mutations if no neurological symptoms have developed. However, significant hypotonia, psychomotor retardation or nystagmus should be contraindications for the liver transplantation [60]. In patients with MPV17, liver transplantation has increased quality and years to life for some patients [61,62], but the patients have developed neurological symptoms. Some children with POLG mutations have received a liver transplant after valproate-induced liver failure, and although it has rescued their liver function, neurological outcome has been unfavorable [63,64].
In patients with MPV17 mutations, a controlled diet avoiding hypoglycemias were suggested to slow down the progression of liver impairment and be useful in supportive care [65]. Some improvement of liver functions in a patient with MPV17 mutations was gained by treating them with succinate or coenzyme-Q10 together with a lipid-rich diet [66]. Further studies with larger patient materials and longer follow-up time are needed to confirm, if these dietary interventions were beneficial, and could be recommended. In MNGIE, correlation between plasma thymidine levels and the severity of the phenotype has been observed [67]. Therefore, attempts to reduce the circulating nucleotide levels could result in disease improvement. Enzyme replacement therapy has been applied for MNGIE: infusion of platelets from healthy donors to patients with MNGIE reduced their circulating thymidine and deoxyuracile levels, and partially restored TP activity. The limitation of this therapy was the short half-life of platelets [68]. Allogenic stem cell transfusions have been given to two patients with MNGIE [69]. Although more experience is needed to illustrate the clinical benefit of that treatment, it opens up a possibility of treatment for disorders of the nucleoside metabolism. In MNGIE, also continuous ambulatory peritoneal dialysis has been used to reduce the thymidine levels, and this resulted in improvement of the symptoms during 3-year follow-up time [70]. Good animal models will enable testing these hypotheses in vivo.
6. Conclusive remarks
The diagnostic process in nuclear disorders of oxidative metabolism is not too different from that employed for other diseases and includes patient and family history, physical and neurologic examination, routine and special laboratory tests, muscle biopsy for morphology and biochemistry, and molecular genetics screening [71]. A mitochondrial disease manifesting at or soon after birth is more likely to be associated with nDNA than with mtDNA mutations, but until very recently, our profound ignorance regarding the mechanisms underlying mitochondrial gene transcription and translation and the complex interaction between the ‘‘2 genomes’’ has limited our diagnostic power. Mitochondrial DNA deletion and depletion syndromes, and disturbances in the mitochondrial translation machinery have become an increasingly important cause of a wide spectrum of infantile and childhood-onset multisystem disorders. Depletion syndromes could result from any imbalance of the mitochondrial dNTPs pools available for mtDNA replication, as well as abnormalities in either the mitochondrial helicase or DNA polymerase. Consistent with the different phenotypes, mtDNA depletion may affect specific tissue (most commonly, brain and muscle or liver) or multiple organs, including the heart and the kidney. Predictably, affected tissues show paucity of mtDNA-encoded translation products and multiple respiratory chain defects. More than 75% of these patients had onset during the first year of life, and the disease was rapidly fatal in most cases [3,72,]. Moreover, though the components of the complicated mitochondrial protein-synthesis machinery are exclusively nuclear encoded, the majority of mutation affects correct translation of mtDNA-encoded subunits of the OXPHOS system and accounts for a still undetermined number of genetic defects. Indeed, there is still limited information on the many mitoribosomal proteins; the several tRNA maturation enzymes; the aminoacyl-tRNA synthetases; the translation initiation, elongation, and termination factors; and the predictably larger number of unidentified factors needed for ribosome assembly [43,73].
The increasing number of nuclear governed mitochondrial diseases and its associated genes continues to increase the diversity of the genetic and clinical phenotypic heterogeneity of this group of disorders. Identifying the causative genes is not only important for adequate genetic counseling and prenatal diagnosis but also to have a better understanding of the disease pathophysiology leading to better therapy options. The increasing number of genes involved is a driving force for the development of high throughput strategies. The recent advances on sequencing technology will facilitate the molecular investigations of genes associated with mtDNA disorders in general. Reports concerning the use of next generation sequencing for the diagnosis of mitochondrial disorders are emerging [74,75,76]. In a recent report the use of target NGS for mitochondrial disorders proved its efficiency in clinical diagnosis as for 55% of the studied patients a clear molecular etiology was found. As more studies are reported the importance of applying this technology will be highlighted.
The problems faced by patients with mitochondrial respiratory chain disease are particularly severe. Diagnosis is difficult, treatment is largely ineffective, genetic counseling and prenatal diagnoses are uncertain or unavailable and the prognosis is unpredictable. Because diagnosis is imperfect and laborious, many patients undergo a whole battery of unnecessary investigations during the diagnostic process. Accurate focused diagnosis will save time, money and distress. Only by understanding the molecular genetic basis of these disorders, whether nuclear or mitochondrial, will any progress be made. Furthermore this will help patients, but will also lead to fundamental advances in our understanding of mitochondrial biology. Identification of new disease-causing gene(s) will hopefully provide insights towards novel therapeutic strategies.
Acknowledgement
The authors would like to thank Prof. Filippo M. Santorelli for providing us Figure 1 of this chapter.
LSA is supported by the Portuguese Foundation for Science and Technology (FCT C2008/INSA/P4). CN is supported by the Portuguese Foundation for Science and Technology (SFRH/BD/45247/2008)
Chapter highlights
The chapter focus on diseases of intergenomic communication disorders mainly the ones involved in mtDNA integrity and mitochondrial protein synthesis
Disorders affecting mtDNA stability lead to multiple deletions or depletion of mtDNA
This group of disorders can affect a variety of organ with variable ages of onset
POLG is frequently mutated being a hotspot for mitochondrial disease
Diagnosis is difficult and laborious due to the increasing number of genes involved
Therapy in mainly palliative however novel strategies are emerging
Due to the increasing number of genes involved novel diagnostic strategies are emerging to optimize the diagnosis offered to these families
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Almeidao, Celia Nogueirao and Laura Vilarinho",authors:[{id:"143595",title:"Prof.",name:"Laura",middleName:null,surname:"Vilarinho",fullName:"Laura Vilarinho",slug:"laura-vilarinho",email:"laura.vilarinho@insa.min-saude.pt",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"143596",title:"Dr.",name:"Celia",middleName:null,surname:"Nogueira",fullName:"Celia Nogueira",slug:"celia-nogueira",email:"celia.nogueira@insa.min-saude.pt",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"143597",title:"Prof.",name:"Ligia",middleName:null,surname:"Almeida",fullName:"Ligia Almeida",slug:"ligia-almeida",email:"ligia.almeida@insa.min-saude.pt",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Clinical manifestations of disorders affecting mtDNA integrity",level:"1"},{id:"sec_2_2",title:"2.1. mtDNA multiple deletion syndromes",level:"2"},{id:"sec_3_2",title:"2.2. mtDNA depletion syndromes",level:"2"},{id:"sec_5",title:"3. Molecular etiologies of disorders affecting mtDNA integrity",level:"1"},{id:"sec_5_2",title:"3.1. Genes involved in mitochondrial replisome",level:"2"},{id:"sec_5_3",title:"3.1.1. POLG",level:"3"},{id:"sec_6_3",title:"3.1.2. POLG2 ",level:"3"},{id:"sec_7_3",title:"3.1.3. C10orf2 (Twinkle)",level:"3"},{id:"sec_9_2",title:"3.2. Genes involved in the synthesis and supply of nucleotide pools",level:"2"},{id:"sec_9_3",title:"3.2.1. SLC25A4",level:"3"},{id:"sec_10_3",title:"3.2.2. SLC25A3",level:"3"},{id:"sec_11_3",title:"3.2.3. Tymp (ECGF1) ",level:"3"},{id:"sec_12_3",title:"3.2.4. TK2",level:"3"},{id:"sec_13_3",title:"3.2.5. DGUOK",level:"3"},{id:"sec_14_3",title:"3.2.6. RRM2B",level:"3"},{id:"sec_15_3",title:"3.2.7. MPV17",level:"3"},{id:"sec_16_3",title:"3.2.8. SUCLA2 and SUCLG1",level:"3"},{id:"sec_18_2",title:"3.3. Genes involved in mitochondrial translation",level:"2"},{id:"sec_18_3",title:"3.3.1. Genes involved in mitochondrial translation factors",level:"3"},{id:"sec_19_3",title:"3.3.2. Genes involved in mitochondrial aminoacyl tRNA synthetases",level:"3"},{id:"sec_22",title:"4. Diagnostic approaches for intergenomic communication disorders",level:"1"},{id:"sec_23",title:"5. Therapeutic considerations",level:"1"},{id:"sec_24",title:"6. Conclusive remarks",level:"1"},{id:"sec_25",title:"Acknowledgement",level:"1"},{id:"sec_26",title:"Chapter highlights",level:"1"}],chapterReferences:[{id:"B1",body:'Schaefer AM, Taylor RW, Turnbull DM, Chinnery PF2004The epidemiology of mitochondrial disorders-past, present and future. Biochim Biophys Acta. 1659 (2-3): 115-120.'},{id:"B2",body:'Schapira AH2006Mitochondrial disease. Lancet. 3687082'},{id:"B3",body:'HiranoM.MartiR.Ferreiro-BarrosC.VilàM. 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A.HerbergU.HennermannJ. B.KlopstockT.KuhnK. A.AhtingU.SperlW.WilichowskiE.HoffmannG. F.TesarovaM.HansikovaH.ZemanJ.PleckoB.ZevianiM.WittigI.StromT. M.SchuelkeM.FreisingerP.MeitingerT.ProkischH.2012Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing. J Med Genet. 494277283'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Ligia S. Almeida",address:null,affiliation:'
Mitochondrial Research Unit, Department of Genetics, National Institute of Health Dr Ricardo Jorge - INSA, Porto, Portugal
Mitochondrial Research Unit, Department of Genetics, National Institute of Health Dr Ricardo Jorge - INSA, Porto, Portugal
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1. Introduction
The pancreatic pathology assessment represents a challenge even today when many imaging techniques are available. The differentiation between chronic pancreatitis and malignant lesions requires sometimes many imaging combined procedures, even histology, without an accurate assessment. The elastography development used the principle that the assessment of a tissue elasticity of tissue might differentiate a benign soft lesion from a malignant hard tissue. But the stiffness assessment and measurement of this small organ, deeply localised in the retroperitoneum, are difficult. High accuracy and reproducibility of pancreatic elastography are not easily obtained, as the histology is not always available [1].
Nowadays both transabdominal ultrasound (US) and endoscopic ultrasound (EUS) allow pancreatic elastography assessment. There are two types of pancreatic elastography: strain elastography and shear wave speed elastography [1]. In the case of strain elastography, the stiffness of pancreatic tissue is estimated by measuring the grade of strain generated by external pressure. For shear speed elastography, the stiffness is estimated by measuring the propagation speed of the shear wave (the transverse wave) generated by acoustic radiation force impulse (ARFI) [1].
The results of elastography can be the strain, which has a negative correlation with tissue stiffness, and the shear wave speed, which has a positive correlation with tissue stiffness [2].
Elastography that measures shear wave speed is classified into shear wave elastography, which uses ARFI as the method to excite shear waves, and transient elastography, in which shear waves are excited in a mechanical manner. Fibroscan™, the only transient elastography device, is not used for the pancreas due to its localization [2]. Shear wave speed might be displayed by two different methods: as the average speed within a small region (target ROI) and as an image reflecting the distribution of the speeds in the ROI [2].
2. Transabdominal ultrasound: strain elastography
The stiffness of pancreatic tissue is estimated through transabdominal ultrasound by measuring the grade of strain generated by aortic pulsation [1, 2, 3, 4]. The relationship between the grade of strain and the stiffness of target tissue is negative correlation: the greater the strain, the softer pancreatic tissue is. For a proper assessment, the target tissue should be located in line between the probe and the aorta [1]. A fine elastogram can be easily obtained in the pancreatic body, except for the patients with severe arteriosclerosis. The elastograms obtained in the pancreatic head and tail should be interpreted with caution [1].
Strain elastography of the pancreas can be obtained with transabdominal ultrasound (US) and with EUS.
First clinical application of US elastography had been reported with real-time tissue elastography™ (RTE) produced by Hitachi Aloka [5, 6]. In the conventional RTE, only qualitative diagnosis using colour map was possible. This technique measures compression-induced tissue deformation (strain) within a region of interest (ROI), which is visualised using a transparent colour overlaying on the B-mode image. In this colour map, the hardest tissue is displayed as blue, and the softest tissue is displayed as red. In RTE, pancreatic cystic lesions cannot be evaluated, due to artefacts, when fluid component of cyst was assessed.
The first report of the usefulness of US elastography for the pancreas in clinical practice was published by Uchida et al. in 2009 [7]. They defined typical colour map observed in US-RTE for different clinical scenarios: homogeneous colour in normal pancreas, markedly hard area with soft spots, was in pancreatic ductal adenocarcinoma, uniform and soft comparable to parenchyma in neuroendocrine tumour and mixture of various colours in chronic pancreatitis. The same authors reported the 70–80% diagnostic accuracy for pancreatic tumours of B-mode alone; when B-mode was combined with US-RTE, the diagnostic accuracy was more than 90% [7].
This qualitative diagnosis using colour map was subjective and highly operator dependent; quantitative diagnosis using strain ratio was established since the second generation of RTE. Strain ratio was defined as the ratio of the strain of reference tissue (B) divided by the strain of target tissue (A).
Strain ratio was adapted from the theory called “fat lesion ratio” reported in the breast, which means the ratio of the strain of fat around the mammary gland divided by the strain of target tissue. The initial principal considered that the stiffness of fat was almost equal in different individuals [1]. To date no consensus exists for the reference area, on non-tumorous area inside the pancreatic parenchyma [8, 9] or on red area around the pancreas, estimated to be fat [10, 11]. There is no evidence if red area around pancreas is really fat. The strain ratios calculated for the same target tissue quite differ according to wherever the reference area is set [1].
The cutoff levels of strain ratio for differential diagnosis between malignant and benign varied in reported studies [9, 10, 11], meaning that pancreatic RTE is highly operator dependent and lacks adequate reproducibility.
A fine B-mode image is required for a fine elastogram, and this is obtained within 6 cm in depth from the body surface in US. Therefore, pancreatic elastogram is quite difficult in the obese. Also B-mode image is easily affected by gastrointestinal gas in US. These problems will occur less frequently in EUS.
Recommendations to obtain a quality elastogram on B-mode US [2]:
The most important is to obtain a quality B-mode images with as few artefacts as possible.
Examination is made from the epigastric fossa in a dorsal position, (semi) sitting position, or left lateral decubitus position.
No vibration should be caused by the probe, which should lightly touch the abdominal wall.
The patient should hold his breath.
Two settings for ROI are accepted [12]: (1) ROI is set only within the target area; (2) ROI is set both within the target area and the surrounding tissue. The second is recommended for neoplastic cancer assessment.
The colours in an elastogram minutely vary with the passage of time according to cardiovascular pulsation. It is desirable that elastograms with good reproducibility are taken at every pulsation by recording the images of elastograms in a range of 5–10 pulsations.
For this type of elastography, emission of ARFI is possible for the entire pancreas. Virtual Touch™ quantification (VTQ) produced by Siemens is a representative instrument. VTQ displays the stiffness of pancreatic tissue digitally shear wave velocity being measured. SWV is expressed in m/s. If an error occurs, X,XX m/s is displayed on the right part of the screen instead of digits [1].
Even if this technique is very promising for the pancreas, there are some issue to be considered. There is a limit to the acoustic radiation force impulse that is certainly safe within the body [2]. Also, when the tissue in the ROI is hard, measurement error tends to occur, because it is difficult to generate sufficient shear waves. When SWV of a pancreatic tumour cannot be assessed, ROI should be placed on a tip of the tumour [2]. If the target area is far from the probe, the attenuation of the focused ultrasound reduces the acoustic radiation force impulse, which in turn reduces the amplitude of the shear waves, making it difficult to detect the shear waves [12]. The safety standards are accomplished by the focused ultrasound [2], but the transmission waveform and wavelength are different from the usual ultrasonic pulses. A concern is represented by its influence on the body, through a possible increase in temperature [13]. Its safety in simultaneous use with contrast media is not confirmed yet [14].
It is recommended to repeat three times the same measurement for the same site about if the reproducibility is high. If the reproducibility is low, a measurement should be repeated 10 times for the same site and the median is used [2].
New ARFI software are developed (ElastPQ™ (Philips), Virtual Touch™ IQ: VTIQ (Siemens)), but their use for the pancreatic pathology is still limited.
Instead the Shear Wave™ Elastography (SWE) (Super Sonic Imaging) uses a new approach. In SWE, ultrasonic beams are continuously emitted to different depths in the tissue, and thus a conically shaped wave surface of shear waves is formed [2]. By an ultrafast imaging method, the shear wave speed is measured. The transducers repeat outgoing/incoming transmissions of ultrasonic waves. A colour map is displayed in the ROI, which can be defined in any location [2]. The mean ± SD, the minimum value, and the maximum value of the shear wave speed in the ROI are displayed. A ratio is calculated when two ROIs in different locations are compared. The study conducted by Arda et al. [15] reported measurement of stiffness for normal pancreas: 11.1 ± 3.2 kPa for males and 10.8 ± 3.1 kPa for females.
The first report of EUS elastography was published in 2005 by Hirooka et al. [5]. Then many papers reported their experience using RTE for pancreatic EUS elastography, being for many years the only system available. In RTE obtained by EUS, the diagnosis is qualitative. It is recommended that the ROI to be set to include peripancreatic tissue [2]. Red colour corresponds to the softest tissue within ROI, and blue corresponds to the hardest tissue within ROI. The remaining tissue is displayed as a coordinated colour between red and blue according to its stiffness. As the colour map depends on the size of ROI in RTE, it is not an absolute one [1].
Some technique aspects should be kept in mind for a qualitative elastogram [2]. The EUS probe should be lightly touching the wall of the stomach or the duodenum. The selected image must be without artefacts. The ultrasonic beam should be towards the aorta, and the strain should be generated in the depth direction. The RTE image should be stably generated for a certain period (5 s or longer in normal cases). For the evaluation of vibration energy, it would be preferable to refer to a strain indicator or to a strain graph. A good-quality B-mode image should be obtained to suit the RTE image [2].
The main debated issue was the differentiation of benign vs. malignant. The diagnostic criteria to differentiate malignancy from benignancy considered two aspects: (1) the dominant colour within colour map and (2) the homogeneity of colour map [1].
In a multicentre study on 121 patients with pancreatic tumours (92 malignant and 29 benign), Giovannini et al. [16] proposed a scoring system: score 1, homogeneous green represents normal tissue; score 2, heterogeneous soft tissue (green, yellow, and red) corresponds to inflammatory tissue; score 3, mixed colour or honeycombed can be attributed to any pathology; score 4, small green central area surrounded by mainly blue; and score 5, mainly blue with heterogeneous green and red, represents advanced malignant lesion. Scores 1 and 2 were considered benign, and scores 4 and 5 were assigned to malignant pathology. The sensitivity and specificity for this score were 92.3 and 80% [16].
The (semi) quantitative evaluation is possible, being more objective, but the analytical procedure is complicated. The image quantitative analysis reported included strain ratio [9, 10, 17], strain histogram [18, 19], and neural network [20, 21, 22]. A comparison between different analysis methods has not been conducted, so there is no consensus about which of these methods is the best.
5. Clinical applications for pancreatic elastography
Uchida et al. [7] published the first report evaluating the usefulness of US elastography for the pancreas in 2009. They reviewed elastograms performed for 10 normal pancreas and reported the typical colour map for normal pancreas assessed by RTE as homogeneous colour.
The normal reference values of pancreas stiffness using ARFI elastography through Virtual Touch Tissue Quantification (Siemens) were reported by Zaro et al. in 2016 [23]: from the entire parenchyma—1.216 m/s ± 0.36 (head, 1.224 m/s; body, 1.227 m/s; and tail, 1.191 m/s) [23]. Another study found a significant correlation between increasing age and elastographic parameters [24]. Using SWE (Super Sonic Imaging) Arda et al. [15] reported measurement of stiffness for normal pancreas: 11.1 ± 3.2 kPa for males and 10.8 ± 3.1 kPa for females.
6. Benign vs. malignant mass pancreatic lesions
The most frequent use of elastography in pancreatic pathology is for differential diagnosis between benign and malignant focal lesions.
The number of reports on strain elastography with US is extremely small in comparison with EUS.
Uchida et al. [7] used strain elastography with US to evaluate the colour patterns of the pancreatic cancers, pancreatic endocrine tumours, and chronic pancreatitis. They concluded that adding strain elastography to the B-mode observations the diagnosis sensitivity is improved [7]. Kawada et al. [8] reported the use of strain ratio to distinguish between malignancy and benignancy of pancreatic solid tumours. The evaluation of the pancreatic tumours by transabdominal shear wave elastography was reported by Zaro et al. [25] in a pilot studied. The mean SWV of the pathological parenchyma indicated an increase of the SWV at the tumoral (cephalic) level corresponding to 1.54 ± 0.32 m/s compared to 1.21 ± 0.27 m/s for normal pancreas in the control group. Future research is needed to validate this data.
Most reports regarding EUS elastography for the pancreas are associated with the differential diagnosis between benign and malignant solid pancreatic tumours, being published several meta-analyses related to the differential diagnosis of pancreatic tumours [26, 27]. Elastograms for pancreatic adenocarcinoma and neuroendocrine tumours are displayed in Figures 1 and 2.
Figure 1.
Advanced pancreatic adenocarcinoma assessed by EUS-RTE. Elastogram is mainly blue with heterogeneous green and red corresponding to score 5 from Giovannini classification.
Figure 2.
Small neuroendocrine tumour at the tail of the pancreas assessed by EUS-RTE. Elastogram depicts heterogeneous small points surrounded by mainly blue corresponding to score 4 from Giovannini classification.
The sensitivity of EUS elastography for the differential diagnosis of pancreatic tumours is reported to be excellent ranging from 95 to 99%, while its specificity is reported to be inadequate ranging from 67 to 76% [1, 26, 27]. This low specificity is explained by the increased stiffness of benign nodule from chronic pancreatitis due to severe fibrosis. Fine needle aspiration through EUS is still mandatory even in cases with proper assessment of pancreatic tissue stiffness. There are few selective cases in which EUS-FNA cannot be performed, and the malignant diagnosis arguments include elastography [28]. But consensus criteria for differential diagnosis between malignant and benign pancreatic tumours were not established.
In clinical practice there are many challenging diagnosis. The images obtained with EUS elastography should be integrated in the clinical context of the patient, being complementary to other imaging techniques. Small tumour-like images, with suggestive malignant features at elastogram, should be interpreted with caution. To assess the quality and reproducibility of the elastography image, a consistent colour pattern obtained in a number of consecutive frames is indicated. If there are different elastograms obtained for the same tumour-like image (Figure 3a–c), all the technical adjustments should be rechecked.
Figure 3.
(a) EUS B-mode. Dilated common bile duct and suspicion of periampular tumour. (b) A “tumour-like image, suspected of malignancy” on elastogram, due to its blue (hard) appearance. This false elastogram is due to the angulations of distal tip of echo-endoscope. (c) A correct assessment of the stiffness of the ampular region displays a mixed inflamed tissue: heterogeneous soft tissue (green and red) corresponding to score 2 in Giovannini classification.
7. Chronic pancreatitis
Chronic pancreatitis is frequently diagnosed in advance stages. Echo-endoscopy may be a useful method for the early diagnosis of chronic pancreatitis, even its diagnostic criteria are operator dependent.
Shear wave elastography using transabdominal US might be an objective and noninvasive method for the early diagnosis of pancreatic fibrosis. Yashima et al. [29] subjected 46 patients with chronic pancreatitis and 52 normal pancreas and measured SWV at the head, the body, and the tail of the pancreas for 10 times in each case and reported a sensitivity of 75% and a specificity of 72% for detection of chronic pancreatitis. They also determined the cutoff of SWV optimal for diagnosing chronic pancreatitis as 1.40 m/s by ROC analysis. Multivariate analysis detected that severe alcohol intake (OR = 3.87, p = 0.005) and deeper depth of the pancreas from the body surface ≥4.2 cm (OR = 0.10, p = 0.002) were associated with the stiffness of the pancreas (>1.40 m/s) [12]. Kuwahara et al. [30] reported that chronic pancreatitis might be diagnosed noninvasively and objectively using SW-EG without performing EUS, the diagnosis accuracy being 77%.
Many reports evaluated the accuracy of EUS elastography for the diagnosis of pancreatic fibrosis. An elastogram in a patient with chronic pancreatitis is displayed in Figure 4. Itoh et al. [18] performed EUS elastography preoperatively for the proximal side of the pancreatic tumour and compared the elastograms with microscopic findings of the resected specimens. They found significant correlation between objective parameters assessed by elastography (mean, standard deviation, skewness, kurtosis) and the grade of fibrosis evaluated by histology. Iglesias-Garcia et al. [31] reported a positive correlation between strain ratio and Rosemont classification (r = 0.813, p < 0.0001).
Figure 4.
An elastogram of chronic pancreatitis: heterogeneous soft tissue (green, yellow, and red) corresponding to score 2 in Giovannini classification.
EUS elastography could predict pancreatic exocrine dysfunction in patients with chronic pancreatitis [32]. Iglesias-Garcia et al. [31] found significant correlation between strain ratio and pancreatic exocrine dysfunction evaluated by 13C-mixed triglyceride breath test.
In autoimmune pancreatitis the specific elastogram detected in five cases was homogenous stiffness of the whole organ, different from the circumscribed mass lesion in ductal adenocarcinoma [33].
8. Prediction of pancreatic fistula after pancreatic surgery
There are studies reporting that the stiffness of the pancreas measured preoperatively could predict the incidence of postoperative pancreatic juice fistula [34, 35, 36]. The postoperative fistula was observed more frequently in patients with lower stiffness of the pancreas (SWV < 1.54 m/s) than in patients with higher stiffness of the pancreas (63 vs. 17%, p < 0.001) [34].
9. Conclusions
The aim of pancreatic elastography for the pancreas is to reflect accurately the histological structure. The pancreatic elastography is challenging, as the access to this small organ is not easy, deep in the centre of the body. Also the biopsy specimens are difficult to obtain for direct comparison. Many of the challenges were resolved by the new technical achievements in the recent years. Both transabdominal US and EUS elastography might offer the clinicians an important tool for depiction of early chronic pancreatitis and a reliable tool for differential diagnosis between malignant and benign pancreatic masses.
\n',keywords:"pancreas, elastography, pancreatic cancer, chronic pancreatitis",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/70435.pdf",chapterXML:"https://mts.intechopen.com/source/xml/70435.xml",downloadPdfUrl:"/chapter/pdf-download/70435",previewPdfUrl:"/chapter/pdf-preview/70435",totalDownloads:736,totalViews:0,totalCrossrefCites:0,dateSubmitted:"May 14th 2019",dateReviewed:"September 30th 2019",datePrePublished:"December 12th 2019",datePublished:"March 4th 2020",dateFinished:"December 12th 2019",readingETA:"0",abstract:"Pancreatic elastography represents a challenging new procedure for inflammatory pathology or tumour masses. There are technical difficulties for accurate assessment of pancreatic stiffness due to deep localization. But the new software for both conventional and endoscopic ultrasound are promising techniques for differential diagnosis between malignant tumours and different forms of chronic pancreatitis (groove pancreatitis or autoimmune pancreatitis). Early diagnosis of chronic pancreatitis, noninvasively by transabdominal shear wave elastography, is actively studied nowadays. Elastography might offer a predictive tool for the occurrence of pancreatic fistula after pancreatoduodenectomy. This chapter introduces the recent innovation of pancreatic elastography and makes recommendations for its use.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/70435",risUrl:"/chapter/ris/70435",signatures:"Lidia Ciobanu",book:{id:"8691",type:"book",title:"Ultrasound Elastography",subtitle:null,fullTitle:"Ultrasound Elastography",slug:"ultrasound-elastography",publishedDate:"March 4th 2020",bookSignature:"Monica Lupsor-Platon",coverURL:"https://cdn.intechopen.com/books/images_new/8691.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-78985-710-8",printIsbn:"978-1-78985-709-2",pdfIsbn:"978-1-83880-015-4",isAvailableForWebshopOrdering:!0,editors:[{id:"208594",title:"Associate Prof.",name:"Monica",middleName:null,surname:"Lupsor-Platon",slug:"monica-lupsor-platon",fullName:"Monica Lupsor-Platon"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"217116",title:"Dr.",name:"Lidia",middleName:null,surname:"Ciobanu",fullName:"Lidia Ciobanu",slug:"lidia-ciobanu",email:"ciobanulidia@yahoo.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Iuliu Hațieganu University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Transabdominal ultrasound: strain elastography",level:"1"},{id:"sec_3",title:"3. Transabdominal ultrasound: shear wave elastography",level:"1"},{id:"sec_4",title:"4. Echo-endoscopy elastography: strain elastography",level:"1"},{id:"sec_5",title:"5. Clinical applications for pancreatic elastography",level:"1"},{id:"sec_6",title:"6. Benign vs. malignant mass pancreatic lesions",level:"1"},{id:"sec_7",title:"7. Chronic pancreatitis",level:"1"},{id:"sec_8",title:"8. Prediction of pancreatic fistula after pancreatic surgery",level:"1"},{id:"sec_9",title:"9. Conclusions",level:"1"}],chapterReferences:[{id:"B1",body:'Kawada N, Tanaka S. Elastography for the pancreas: Current status and future perspective. World Journal of Gastroenterology. 14 Apr 2016;22(14):3712-3724'},{id:"B2",body:'Hirooka Y, Kuwahara T, Irisawa A, Itokawa F, Uchida H, Sasahira N, et al. JSUM ultrasound elastography practice guidelines: Pancreas. Journal of Medical Ultrasonics (2001). 2015;42:151-174. DOI: 10.1007/s10396-014-0571-7'},{id:"B3",body:'Shiina T, Doyley MM, Bamber JC. Strain imaging using combined RF and envelope autocorrelation processing. In: Proceeding of the 1996 IEEE Int Ultrasonics Symposium. San Antonio: IEEE; 1996. DOI: 10.1109/ULTSYM.1996.584292'},{id:"B4",body:'Shiina T, Yamakawa M, Nitta N. Recent prognosis of ultrasound elasticity imaging technology. International Congress Series. 2004;1274:59-63. DOI: 10.1016/j.ics.2004.07.054'},{id:"B5",body:'Hirooka Y, Itoh A, Hashimoto S. Utility of EIS: Elastography in the diagnosis of pancreatic diseases. Gastrointestinal Endoscopy. 2005;61:AB282. DOI: 10.1016/S0016-5107(05)01447-1'},{id:"B6",body:'Uchida H, Hirooka Y, Ito A, Hashimoto S, Kawashima H, Hara K, et al. Utility of elastography in the diagnosis of pancreatic diseases using transabdominal ultrasonography. Gastroenterology. 2005;128:A536'},{id:"B7",body:'Uchida H, Hirooka Y, Itoh A, Kawashima H, Hara K, Nonogaki K, et al. Feasibility of tissue elastography using transcutaneous ultrasonography for the diagnosis of pancreatic diseases. Pancreas. 2009;38:17-22. DOI: 10.1097/MPA.0b013e318184db78'},{id:"B8",body:'Kawada N, Tanaka S, Uehara H, Takakura R, Katayama K, Fukuda J, et al. Feasibility of second-generation transabdominal ultrasound-elastography to evaluate solid pancreatic tumors: Preliminary report of 36 cases. Pancreas. 2012;41:978-980. DOI: 10.1097/MPA.0b013e3182499b84'},{id:"B9",body:'Itokawa F, Itoi T, Sofuni A, Kurihara T, Tsuchiya T, Ishii K, et al. EUS elastography combined with the strain ratio of tissue elasticity for diagnosis of solid pancreatic masses. Journal of Gastroenterology. 2011;46:843-853. DOI: 10.1007/s00535-011-0399-5'},{id:"B10",body:'Iglesias-Garcia J, Larino-Noia J, Abdulkader I, Forteza J, Dominguez-Munoz JE. Quantitative endoscopic ultrasound elastography: An accurate method for the differentiation of solid pancreatic masses. Gastroenterology. 2010;139:1172-1180. DOI: 10.1053/j.gastro.2010.06.059'},{id:"B11",body:'Dawwas MF, Taha H, Leeds JS, Nayar MK, Oppong KW. Diagnostic accuracy of quantitative EUS elastography for discriminating malignant from benign solid pancreatic masses: A prospective, single-center study. Gastrointestinal Endoscopy. 2012;76:953-961. DOI: 10.1016/j.gie.2012.05.034'},{id:"B12",body:'Kawada N, Tanaka S, Uehara H, et al. Potential use of point shear wave elastography for the pancreas: A single center prospective study. European Journal of Radiology. 2014;83:620-624'},{id:"B13",body:'Herman BA, Harris GR. Models and regulatory considerations for transient temperature rise during diagnostic ultrasound pulses. Ultrasound in Medicine & Biology. 2002;28:1217-1224'},{id:"B14",body:'Barnett SB, Duck F, Ziskin M. Recommendations on the safe use of ultrasound contrast agents. Ultrasound in Medicine & Biology. 2007;33:173-174'},{id:"B15",body:'Arda K, Ciledag N, Aktas E, et al. Quantitative assessment of normal soft-tissue elasticity using shear-wave ultrasound elastography. AJR. American Journal of Roentgenology. 2011;197:532-536'},{id:"B16",body:'Giovannini M, Thomas B, Erwan B, Christian P, Fabrice C, Benjamin E, et al. Endoscopic ultrasound elastography for evaluation of lymph nodes and pancreatic masses: A multicentre study. World Journal of Gastroenterology. 2009;15:1587-1593. DOI: 10.3748/wjg.15.1587'},{id:"B17",body:'Mayerle J, Simon P, Dickson EJ, et al. The role of EUS guided elastography to diagnose solid pancreatic mass lesions. Pancreas. 2010;39:1334'},{id:"B18",body:'Itoh Y, Itoh A, Kawashima H, et al. Quantitative analysis of diagnosing pancreatic fibrosis using EUS-elastography (comparison with surgical specimens). Journal of Gastroenterology. 2014;49:1183-1192'},{id:"B19",body:'Janssen J, Papavassiliou I. Effect of aging and diffuse chronic pancreatitis on pancreas elasticity evaluated using semiquantitative EUS elastography. Ultraschall in der Medizin. 2014;35:253-258'},{id:"B20",body:'Saftoiu A, Vilmann P, Gorunescu F, et al. Accuracy of endoscopic ultrasound elastography used for differential diagnosis of focal pancreatic masses: A multicenter study. Endoscopy. 2011;43:596-603'},{id:"B21",body:'Saftoiu A, Vilman P, Gorunescu F, et al. Neural network analysis of dynamic sequences of EUS elastography used for the differential diagnosis of chronic pancreatitis and pancreatic cancer. Gastrointestinal Endoscopy. 2008;68:1086-1094'},{id:"B22",body:'Saftoiu A, Iordache S, Gheonea DI, et al. Combined contrast-enhanced power doppler and real-time sonoelastography performed during EUS, used in the differential diagnosis of focal pancreatic masses (with videos). Gastrointestinal Endoscopy. 2010;72:739-747'},{id:"B23",body:'Zaro R, Lupsor-Platon M, Cheviet A, Badea R. The pursuit of normal reference values of pancreas stiffness by using acoustic radiation force impulse (ARFI) elastography. Medical Ultrasonography. 2016;18(4):425-430'},{id:"B24",body:'Chantarojanasiri T, Hirooka Y, Kawashima H, Ohno E, Sugimoto H, Hayashi D, et al. Age-related changes in pancreatic elasticity: When should we be concerned about their effect on strain elastography? Ultrasonics. 2016;69:90-96'},{id:"B25",body:'Zaro R, Dina L, Pojoga C, Vesa S, Badea R. Evaluation of the pancreatic tumors by transabdominal shear wave elastography: Preliminary results of a pilot study. Medical Ultrasonography. 2018;20(3):285-291'},{id:"B26",body:'Mei M, Ni J, Liu D, et al. EUS elastography for diagnosis of solid pancreatic masses: A meta-analysis. Gastrointestinal Endoscopy. 2013;77:578-589'},{id:"B27",body:'Pei Q , Zou X, Zhang X, et al. Diagnostic value of EUS elastography in differentiation of benign and malignant solid pancreatic masses: A meta-analysis. Pancreatology. 2012;12:402-408'},{id:"B28",body:'Popescu A, Săftoiu A. Can elastography replace fine needle aspiration? Endosc Ultrasound. 2014;3:109-117. DOI: 10.4103/2303-9027.123009'},{id:"B29",body:'Yashima Y, Sasahira N, Isayama H, Kogure H, Ikeda H, Hirano K, et al. Acoustic radiation force impulse elastography for noninvasive assessment of chronic pancreatitis. Journal of Gastroenterology. 2012;47:427-432. DOI: 10.1007/s00535-011-0491-x'},{id:"B30",body:'Kuwahara T, Hirooka Y, Kawashima H, Ohno E, Ishikawa T, Yamamura T, et al. Usefulness of shear wave elastography as a quantitative diagnosis of chronic pancreatitis. Journal of Gastroenterology and Hepatology. Mar 2018;33(3):756-761'},{id:"B31",body:'Iglesias-Garcia J, Domínguez-Muñoz JE, Castiñeira-Alvariño M, Luaces-Regueira M, Lariño-Noia J. Quantitative elastography associated with endoscopic ultrasound for the diagnosis of chronic pancreatitis. Endoscopy. 2013;45:781-788. DOI: 10.1055/s-0033-1344614'},{id:"B32",body:'Domínguez-Muñoz JE, Alvarez-Castro A, Lariño-Noia J, Nieto L, Iglesias-García J. Endoscopic ultrasonography of the pancreas as an indirect method to predict pancreatic exocrine insufficiency in patients with chronic pancreatitis. Pancreas. 2012;41:724-728. DOI: 10.1097/MPA.0b013e31823b5978'},{id:"B33",body:'Dietrich CF, Hirche TO, Ott M, Ignee A. Real-time tissue elastography in the diagnosis of autoimmune pancreatitis. Endoscopy. 2009;41:718-720'},{id:"B34",body:'Harada N, Ishizawa T, Inoue Y, Aoki T, Sakamoto Y, Hasegawa K, et al. Acoustic radiation force impulse imaging of the pancreas for estimation of pathologic fibrosis and risk of postoperative pancreatic fistula. Journal of the American College of Surgeons. 2014;219:887-894.e5. DOI: 10.1016/j.jamcollsurg.2014.07.940'},{id:"B35",body:'Hatano M, Watanabe J, Kushihata F, Tohyama T, Kuroda T, Koizumi M, et al. Quantification of pancreatic stiffness on intraoperative ultrasound elastography and evaluation of its relationship with postoperative pancreatic fistula. International Surgery. 2015;100:497-502. DOI: 10.9738/INTSURG-D-14-00040.1'},{id:"B36",body:'Lee TK, Kang CM, Park MS, Choi SH, Chung YE, Choi JY, et al. Prediction of postoperative pancreatic fistulas after pancreatectomy: Assessment with acoustic radiation force impulse elastography. Journal of Ultrasound in Medicine. 2014;33:781-786. DOI: 10.7863/ultra.33.5.781'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Lidia Ciobanu",address:"ciobanulidia@yahoo.com",affiliation:'
Iuliu Hatieganu University of Medicine and Pharmacy, Regional Institute of Gastroenterology and Hepatology, Cluj-Napoca, Romania
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IntechOpen implements a robust policy to minimize and deal with instances of fraud or misconduct. As part of our general commitment to transparency and openness, and in order to maintain high scientific standards, we have a well-defined editorial policy regarding Retractions and Corrections.
",metaTitle:"Retraction and Correction Policy",metaDescription:"Retraction and Correction Policy",metaKeywords:null,canonicalURL:"/page/retraction-and-correction-policy",contentRaw:'[{"type":"htmlEditorComponent","content":"
IntechOpen’s Retraction and Correction Policy has been developed in accordance with the Committee on Publication Ethics (COPE) publication guidelines relating to scientific misconduct and research ethics:
\\n\\n
1. RETRACTIONS
\\n\\n
A Retraction of a Chapter will be issued by the Academic Editor, either following an Author’s request to do so or when there is a 3rd party report of scientific misconduct. Upon receipt of a report by a 3rd party, the Academic Editor will investigate any allegations of scientific misconduct, working in cooperation with the Author(s) and their institution(s).
\\n\\n
A formal Retraction will be issued when there is clear and conclusive evidence of any of the following:
\\n\\n
\\n\\t
Data fabrication
\\n\\t
Data recycling in a purportedly original research article
\\n\\t
Severe plagiarism - whether or not the plagiarism is to be deemed severe will be determined by the Academic Editor and verified by plagiarism checking software
\\n\\t
Double publication
\\n\\t
Copyright infringement - for example, if a Chapter uses copyrighted figures without permission.
\\n\\t
Unreliable findings
\\n\\t
Unethical research practices
\\n\\t
Any other practice or act considered potentially harmful to the scientific community.
\\n
\\n\\n
Publishing of a Retraction Notice will adhere to the following guidelines:
\\n\\n\\n\\t
All relevant bibliographic information about a retracted Chapter will be given in the title.
\\n\\t
A Retraction Notice will be published as a regular book Chapter and will be given its own Chapter number.
\\n\\n\\n
\\n\\t
Authors shall be required to approve a proposed retraction of their Chapter. If Authors maintain that their Chapter should not be retracted, the Academic Editor may issue a Statement of Concern (see 2. below).
\\n
\\n\\n
1.2. REMOVALS AND CANCELLATIONS
\\n\\n
\\n\\t
Additionally, a Chapter retracted on grounds of copyright infringement (e.g. double publication) may be Removed by the publisher should the original copyright owner request such action. A Chapter retracted on grounds of its potential to harm the scientific community, for example, when a Chapter is defamatory in nature, may also be subject to removal.
\\n\\t
No formal Removal Notice will be published but a notice citing the reason for removal will be prominently displayed in place of a retracted and subsequently removed Chapter.
\\n\\t
Chapters published due to inadvertent production mistakes shall be canceled and the cancellation notice will be published.
\\n
\\n\\n
2. STATEMENTS OF CONCERN
\\n\\n
A Statement of Concern detailing alleged misconduct will be issued by the Academic Editor or publisher following a 3rd party report of scientific misconduct when:
\\n\\n
\\n\\t
Authors refuse to approve a retraction proposed by the Academic Editor
\\n\\t
There is inconclusive evidence of scientific misconduct
\\n\\t
Authors and their respective institutions fail or refuse to provide adequate assistance in an investigation
\\n\\t
The publication of a Statement of Concern will adhere to the Retraction Notice guidelines outlined above
\\n\\t
An article PDF for which a Statement of Concern is published will remain available online without being edited or watermarked
\\n
\\n\\n
IntechOpen believes that the number of occasions on which a Statement of Concern is issued will be very few in number. In all cases when such a decision has been taken by the Academic Editor the decision will be reviewed by another editor to whom the author can make representations.
\\n\\n
3. CORRECTIONS
\\n\\n
A Correction will be issued by the Academic Editor when:
\\n\\n
\\n\\t
Only a small portion of a Chapter is flawed in a way that does not severely affect any findings.
\\n\\t
It is determined that the scientific community would be better served by a Correction rather than a Retraction.
\\n\\t
Corrections will be issued in one of two distinct forms -- ERRATUM or CORRIGENDUM, depending on the origin of a mistake.
\\n
\\n\\n
3.1. ERRATUM
\\n\\n
An Erratum will be issued by the Academic Editor when it is determined that a mistake in a Chapter originates from the production process handled by the publisher.
\\n\\n
A published Erratum will adhere to the Retraction Notice publishing guidelines outlined above.
\\n\\n
3.2. CORRIGENDUM
\\n\\n
A Corrigendum will be issued by the Academic Editor when it is determined that a mistake in a Chapter is a result of an Author’s miscalculation or oversight. A published Corrigendum will adhere to the Retraction Notice publishing guidelines outlined above.
\\n\\n
4. FINAL REMARKS
\\n\\n
IntechOpen wishes to emphasize that the final decision on whether a Retraction, Statement of Concern, or a Correction will be issued rests with the Academic Editor. The publisher is obliged to act upon any reports of scientific misconduct in its publications and to make a reasonable effort to facilitate any subsequent investigation of such claims.
\\n\\n
In the case of Retraction or removal of the Work, the publisher will be under no obligation to refund the APC.
\\n\\n
The general principles set out above apply to Retractions and Corrections issued in all IntechOpen publications.
IntechOpen’s Retraction and Correction Policy has been developed in accordance with the Committee on Publication Ethics (COPE) publication guidelines relating to scientific misconduct and research ethics:
\n\n
1. RETRACTIONS
\n\n
A Retraction of a Chapter will be issued by the Academic Editor, either following an Author’s request to do so or when there is a 3rd party report of scientific misconduct. Upon receipt of a report by a 3rd party, the Academic Editor will investigate any allegations of scientific misconduct, working in cooperation with the Author(s) and their institution(s).
\n\n
A formal Retraction will be issued when there is clear and conclusive evidence of any of the following:
\n\n
\n\t
Data fabrication
\n\t
Data recycling in a purportedly original research article
\n\t
Severe plagiarism - whether or not the plagiarism is to be deemed severe will be determined by the Academic Editor and verified by plagiarism checking software
\n\t
Double publication
\n\t
Copyright infringement - for example, if a Chapter uses copyrighted figures without permission.
\n\t
Unreliable findings
\n\t
Unethical research practices
\n\t
Any other practice or act considered potentially harmful to the scientific community.
\n
\n\n
Publishing of a Retraction Notice will adhere to the following guidelines:
\n\n\n\t
All relevant bibliographic information about a retracted Chapter will be given in the title.
\n\t
A Retraction Notice will be published as a regular book Chapter and will be given its own Chapter number.
\n\n\n
\n\t
Authors shall be required to approve a proposed retraction of their Chapter. If Authors maintain that their Chapter should not be retracted, the Academic Editor may issue a Statement of Concern (see 2. below).
\n
\n\n
1.2. REMOVALS AND CANCELLATIONS
\n\n
\n\t
Additionally, a Chapter retracted on grounds of copyright infringement (e.g. double publication) may be Removed by the publisher should the original copyright owner request such action. A Chapter retracted on grounds of its potential to harm the scientific community, for example, when a Chapter is defamatory in nature, may also be subject to removal.
\n\t
No formal Removal Notice will be published but a notice citing the reason for removal will be prominently displayed in place of a retracted and subsequently removed Chapter.
\n\t
Chapters published due to inadvertent production mistakes shall be canceled and the cancellation notice will be published.
\n
\n\n
2. STATEMENTS OF CONCERN
\n\n
A Statement of Concern detailing alleged misconduct will be issued by the Academic Editor or publisher following a 3rd party report of scientific misconduct when:
\n\n
\n\t
Authors refuse to approve a retraction proposed by the Academic Editor
\n\t
There is inconclusive evidence of scientific misconduct
\n\t
Authors and their respective institutions fail or refuse to provide adequate assistance in an investigation
\n\t
The publication of a Statement of Concern will adhere to the Retraction Notice guidelines outlined above
\n\t
An article PDF for which a Statement of Concern is published will remain available online without being edited or watermarked
\n
\n\n
IntechOpen believes that the number of occasions on which a Statement of Concern is issued will be very few in number. In all cases when such a decision has been taken by the Academic Editor the decision will be reviewed by another editor to whom the author can make representations.
\n\n
3. CORRECTIONS
\n\n
A Correction will be issued by the Academic Editor when:
\n\n
\n\t
Only a small portion of a Chapter is flawed in a way that does not severely affect any findings.
\n\t
It is determined that the scientific community would be better served by a Correction rather than a Retraction.
\n\t
Corrections will be issued in one of two distinct forms -- ERRATUM or CORRIGENDUM, depending on the origin of a mistake.
\n
\n\n
3.1. ERRATUM
\n\n
An Erratum will be issued by the Academic Editor when it is determined that a mistake in a Chapter originates from the production process handled by the publisher.
\n\n
A published Erratum will adhere to the Retraction Notice publishing guidelines outlined above.
\n\n
3.2. CORRIGENDUM
\n\n
A Corrigendum will be issued by the Academic Editor when it is determined that a mistake in a Chapter is a result of an Author’s miscalculation or oversight. A published Corrigendum will adhere to the Retraction Notice publishing guidelines outlined above.
\n\n
4. FINAL REMARKS
\n\n
IntechOpen wishes to emphasize that the final decision on whether a Retraction, Statement of Concern, or a Correction will be issued rests with the Academic Editor. The publisher is obliged to act upon any reports of scientific misconduct in its publications and to make a reasonable effort to facilitate any subsequent investigation of such claims.
\n\n
In the case of Retraction or removal of the Work, the publisher will be under no obligation to refund the APC.
\n\n
The general principles set out above apply to Retractions and Corrections issued in all IntechOpen publications.
\n'}]},successStories:{items:[]},authorsAndEditors:{filterParams:{},profiles:[{id:"396",title:"Dr.",name:"Vedran",middleName:null,surname:"Kordic",slug:"vedran-kordic",fullName:"Vedran Kordic",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/396/images/7281_n.png",biography:"After obtaining his Master's degree in Mechanical Engineering he continued his education at the Vienna University of Technology where he obtained his PhD degree in 2004. He worked as a researcher at the Automation and Control Institute, Faculty of Electrical Engineering, Vienna University of Technology until 2008. 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On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. 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From 1985 to 1986, he was a Research Fellow in the Research Institute for Electronic Equipment, ZZU AD, Plovdiv, Bulgaria. In 1986, he joined the Department of Control Systems, Technical University of Sofia at the Plovdiv campus, where he is presently a Full Professor. He has held long-term visiting Professor/Scholar positions at various institutions in South Korea, Turkey, Mexico, Greece, Belgium, UK, and Germany. And he has coauthored one book and authored or coauthored more than 80 research papers in conference proceedings and journals. 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Buchholz and Erik J. Behringer",hash:"e373a3d1123dbd45fddf75d90e3e7c38",volumeInSeries:1,fullTitle:"Calcium and Signal Transduction",editors:[{id:"89438",title:"Dr.",name:"John N.",middleName:null,surname:"Buchholz",slug:"john-n.-buchholz",fullName:"John N. Buchholz",profilePictureURL:"https://mts.intechopen.com/storage/users/89438/images/6463_n.jpg",institutionString:null,institution:{name:"Loma Linda University",institutionURL:null,country:{name:"United States of America"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},subseriesFiltersForPublishedBooks:[{group:"subseries",caption:"Plant Physiology",value:13,count:1},{group:"subseries",caption:"Human Physiology",value:12,count:2},{group:"subseries",caption:"Cell Physiology",value:11,count:8}],publicationYearFilters:[{group:"publicationYear",caption:"2022",value:2022,count:1},{group:"publicationYear",caption:"2020",value:2020,count:4},{group:"publicationYear",caption:"2019",value:2019,count:5},{group:"publicationYear",caption:"2018",value:2018,count:1}],authors:{paginationCount:302,paginationItems:[{id:"198499",title:"Dr.",name:"Daniel",middleName:null,surname:"Glossman-Mitnik",slug:"daniel-glossman-mitnik",fullName:"Daniel Glossman-Mitnik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/198499/images/system/198499.jpeg",biography:"Dr. Daniel Glossman-Mitnik is currently a Titular Researcher at the Centro de Investigación en Materiales Avanzados (CIMAV), Chihuahua, Mexico, as well as a National Researcher of Level III at the Consejo Nacional de Ciencia y Tecnología, Mexico. His research interest focuses on computational chemistry and molecular modeling of diverse systems of pharmacological, food, and alternative energy interests by resorting to DFT and Conceptual DFT. He has authored a coauthored more than 255 peer-reviewed papers, 32 book chapters, and 2 edited books. He has delivered speeches at many international and domestic conferences. He serves as a reviewer for more than eighty international journals, books, and research proposals as well as an editor for special issues of renowned scientific journals.",institutionString:"Centro de Investigación en Materiales Avanzados",institution:{name:"Centro de Investigación en Materiales Avanzados",country:{name:"Mexico"}}},{id:"76477",title:"Prof.",name:"Mirza",middleName:null,surname:"Hasanuzzaman",slug:"mirza-hasanuzzaman",fullName:"Mirza Hasanuzzaman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/76477/images/system/76477.png",biography:"Dr. Mirza Hasanuzzaman is a Professor of Agronomy at Sher-e-Bangla Agricultural University, Bangladesh. He received his Ph.D. in Plant Stress Physiology and Antioxidant Metabolism from Ehime University, Japan, with a scholarship from the Japanese Government (MEXT). Later, he completed his postdoctoral research at the Center of Molecular Biosciences, University of the Ryukyus, Japan, as a recipient of the Japan Society for the Promotion of Science (JSPS) postdoctoral fellowship. He was also the recipient of the Australian Government Endeavour Research Fellowship for postdoctoral research as an adjunct senior researcher at the University of Tasmania, Australia. Dr. Hasanuzzaman’s current work is focused on the physiological and molecular mechanisms of environmental stress tolerance. Dr. Hasanuzzaman has published more than 150 articles in peer-reviewed journals. He has edited ten books and written more than forty book chapters on important aspects of plant physiology, plant stress tolerance, and crop production. According to Scopus, Dr. Hasanuzzaman’s publications have received more than 10,500 citations with an h-index of 53. He has been named a Highly Cited Researcher by Clarivate. He is an editor and reviewer for more than fifty peer-reviewed international journals and was a recipient of the “Publons Peer Review Award” in 2017, 2018, and 2019. He has been honored by different authorities for his outstanding performance in various fields like research and education, and he has received the World Academy of Science Young Scientist Award (2014) and the University Grants Commission (UGC) Award 2018. He is a fellow of the Bangladesh Academy of Sciences (BAS) and the Royal Society of Biology.",institutionString:"Sher-e-Bangla Agricultural University",institution:{name:"Sher-e-Bangla Agricultural University",country:{name:"Bangladesh"}}},{id:"187859",title:"Prof.",name:"Kusal",middleName:"K.",surname:"Das",slug:"kusal-das",fullName:"Kusal Das",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSBDeQAO/Profile_Picture_1623411145568",biography:"Kusal K. Das is a Distinguished Chair Professor of Physiology, Shri B. M. Patil Medical College and Director, Centre for Advanced Medical Research (CAMR), BLDE (Deemed to be University), Vijayapur, Karnataka, India. Dr. Das did his M.S. and Ph.D. in Human Physiology from the University of Calcutta, Kolkata. His area of research is focused on understanding of molecular mechanisms of heavy metal activated low oxygen sensing pathways in vascular pathophysiology. He has invented a new method of estimation of serum vitamin E. His expertise in critical experimental protocols on vascular functions in experimental animals was well documented by his quality of publications. He was a Visiting Professor of Medicine at University of Leeds, United Kingdom (2014-2016) and Tulane University, New Orleans, USA (2017). For his immense contribution in medical research Ministry of Science and Technology, Government of India conferred him 'G.P. Chatterjee Memorial Research Prize-2019” and he is also the recipient of 'Dr.Raja Ramanna State Scientist Award 2015” by Government of Karnataka. He is a Fellow of the Royal Society of Biology (FRSB), London and Honorary Fellow of Karnataka Science and Technology Academy, Department of Science and Technology, Government of Karnataka.",institutionString:"BLDE (Deemed to be University), India",institution:null},{id:"243660",title:"Dr.",name:"Mallanagouda Shivanagouda",middleName:null,surname:"Biradar",slug:"mallanagouda-shivanagouda-biradar",fullName:"Mallanagouda Shivanagouda Biradar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243660/images/system/243660.jpeg",biography:"M. S. Biradar is Vice Chancellor and Professor of Medicine of\nBLDE (Deemed to be University), Vijayapura, Karnataka, India.\nHe obtained his MD with a gold medal in General Medicine and\nhas devoted himself to medical teaching, research, and administrations. He has also immensely contributed to medical research\non vascular medicine, which is reflected by his numerous publications including books and book chapters. Professor Biradar was\nalso Visiting Professor at Tulane University School of Medicine, New Orleans, USA.",institutionString:"BLDE (Deemed to be University)",institution:{name:"BLDE University",country:{name:"India"}}},{id:"289796",title:"Dr.",name:"Swastika",middleName:null,surname:"Das",slug:"swastika-das",fullName:"Swastika Das",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/289796/images/system/289796.jpeg",biography:"Swastika N. Das is Professor of Chemistry at the V. P. Dr. P. G.\nHalakatti College of Engineering and Technology, BLDE (Deemed\nto be University), Vijayapura, Karnataka, India. She obtained an\nMSc, MPhil, and PhD in Chemistry from Sambalpur University,\nOdisha, India. Her areas of research interest are medicinal chemistry, chemical kinetics, and free radical chemistry. She is a member\nof the investigators who invented a new modified method of estimation of serum vitamin E. She has authored numerous publications including book\nchapters and is a mentor of doctoral curriculum at her university.",institutionString:"BLDEA’s V.P.Dr.P.G.Halakatti College of Engineering & Technology",institution:{name:"BLDE University",country:{name:"India"}}},{id:"248459",title:"Dr.",name:"Akikazu",middleName:null,surname:"Takada",slug:"akikazu-takada",fullName:"Akikazu Takada",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248459/images/system/248459.png",biography:"Akikazu Takada was born in Japan, 1935. After graduation from\nKeio University School of Medicine and finishing his post-graduate studies, he worked at Roswell Park Memorial Institute NY,\nUSA. He then took a professorship at Hamamatsu University\nSchool of Medicine. In thrombosis studies, he found the SK\npotentiator that enhances plasminogen activation by streptokinase. He is very much interested in simultaneous measurements\nof fatty acids, amino acids, and tryptophan degradation products. By using fatty\nacid analyses, he indicated that plasma levels of trans-fatty acids of old men were\nfar higher in the US than Japanese men. . He also showed that eicosapentaenoic acid\n(EPA) and docosahexaenoic acid (DHA) levels are higher, and arachidonic acid\nlevels are lower in Japanese than US people. By using simultaneous LC/MS analyses\nof plasma levels of tryptophan metabolites, he recently found that plasma levels of\nserotonin, kynurenine, or 5-HIAA were higher in patients of mono- and bipolar\ndepression, which are significantly different from observations reported before. In\nview of recent reports that plasma tryptophan metabolites are mainly produced by\nmicrobiota. He is now working on the relationships between microbiota and depression or autism.",institutionString:"Hamamatsu University School of Medicine",institution:{name:"Hamamatsu University School of Medicine",country:{name:"Japan"}}},{id:"137240",title:"Prof.",name:"Mohammed",middleName:null,surname:"Khalid",slug:"mohammed-khalid",fullName:"Mohammed Khalid",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/137240/images/system/137240.png",biography:"Mohammed Khalid received his B.S. degree in chemistry in 2000 and Ph.D. degree in physical chemistry in 2007 from the University of Khartoum, Sudan. He moved to School of Chemistry, Faculty of Science, University of Sydney, Australia in 2009 and joined Dr. Ron Clarke as a postdoctoral fellow where he worked on the interaction of ATP with the phosphoenzyme of the Na+/K+-ATPase and dual mechanisms of allosteric acceleration of the Na+/K+-ATPase by ATP; then he went back to Department of Chemistry, University of Khartoum as an assistant professor, and in 2014 he was promoted as an associate professor. In 2011, he joined the staff of Department of Chemistry at Taif University, Saudi Arabia, where he is currently an assistant professor. His research interests include the following: P-Type ATPase enzyme kinetics and mechanisms, kinetics and mechanisms of redox reactions, autocatalytic reactions, computational enzyme kinetics, allosteric acceleration of P-type ATPases by ATP, exploring of allosteric sites of ATPases, and interaction of ATP with ATPases located in cell membranes.",institutionString:"Taif University",institution:{name:"Taif University",country:{name:"Saudi Arabia"}}},{id:"63810",title:"Prof.",name:"Jorge",middleName:null,surname:"Morales-Montor",slug:"jorge-morales-montor",fullName:"Jorge Morales-Montor",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/63810/images/system/63810.png",biography:"Dr. Jorge Morales-Montor was recognized with the Lola and Igo Flisser PUIS Award for best graduate thesis at the national level in the field of parasitology. He received a fellowship from the Fogarty Foundation to perform postdoctoral research stay at the University of Georgia. He has 153 journal articles to his credit. He has also edited several books and published more than fifty-five book chapters. He is a member of the Mexican Academy of Sciences, Latin American Academy of Sciences, and the National Academy of Medicine. He has received more than thirty-five awards and has supervised numerous bachelor’s, master’s, and Ph.D. students. Dr. Morales-Montor is the past president of the Mexican Society of Parasitology.",institutionString:"National Autonomous University of Mexico",institution:{name:"National Autonomous University of Mexico",country:{name:"Mexico"}}},{id:"217215",title:"Dr.",name:"Palash",middleName:null,surname:"Mandal",slug:"palash-mandal",fullName:"Palash Mandal",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217215/images/system/217215.jpeg",biography:null,institutionString:"Charusat University",institution:null},{id:"49739",title:"Dr.",name:"Leszek",middleName:null,surname:"Szablewski",slug:"leszek-szablewski",fullName:"Leszek Szablewski",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49739/images/system/49739.jpg",biography:"Leszek Szablewski is a professor of medical sciences. He received his M.S. in the Faculty of Biology from the University of Warsaw and his PhD degree from the Institute of Experimental Biology Polish Academy of Sciences. He habilitated in the Medical University of Warsaw, and he obtained his degree of Professor from the President of Poland. Professor Szablewski is the Head of Chair and Department of General Biology and Parasitology, Medical University of Warsaw. Professor Szablewski has published over 80 peer-reviewed papers in journals such as Journal of Alzheimer’s Disease, Biochim. Biophys. Acta Reviews of Cancer, Biol. Chem., J. Biomed. Sci., and Diabetes/Metabol. Res. Rev, Endocrine. He is the author of two books and four book chapters. He has edited four books, written 15 scripts for students, is the ad hoc reviewer of over 30 peer-reviewed journals, and editorial member of peer-reviewed journals. Prof. Szablewski’s research focuses on cell physiology, genetics, and pathophysiology. He works on the damage caused by lack of glucose homeostasis and changes in the expression and/or function of glucose transporters due to various diseases. He has given lectures, seminars, and exercises for students at the Medical University.",institutionString:"Medical University of Warsaw",institution:{name:"Medical University of Warsaw",country:{name:"Poland"}}},{id:"173123",title:"Dr.",name:"Maitham",middleName:null,surname:"Khajah",slug:"maitham-khajah",fullName:"Maitham Khajah",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/173123/images/system/173123.jpeg",biography:"Dr. Maitham A. Khajah received his degree in Pharmacy from Faculty of Pharmacy, Kuwait University, in 2003 and obtained his PhD degree in December 2009 from the University of Calgary, Canada (Gastrointestinal Science and Immunology). Since January 2010 he has been assistant professor in Kuwait University, Faculty of Pharmacy, Department of Pharmacology and Therapeutics. His research interest are molecular targets for the treatment of inflammatory bowel disease (IBD) and the mechanisms responsible for immune cell chemotaxis. He cosupervised many students for the MSc Molecular Biology Program, College of Graduate Studies, Kuwait University. Ever since joining Kuwait University in 2010, he got various grants as PI and Co-I. He was awarded the Best Young Researcher Award by Kuwait University, Research Sector, for the Year 2013–2014. He was a member in the organizing committee for three conferences organized by Kuwait University, Faculty of Pharmacy, as cochair and a member in the scientific committee (the 3rd, 4th, and 5th Kuwait International Pharmacy Conference).",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"195136",title:"Dr.",name:"Aya",middleName:null,surname:"Adel",slug:"aya-adel",fullName:"Aya Adel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/195136/images/system/195136.jpg",biography:"Dr. Adel works as an Assistant Lecturer in the unit of Phoniatrics, Department of Otolaryngology, Ain Shams University in Cairo, Egypt. Dr. Adel is especially interested in joint attention and its impairment in autism spectrum disorder",institutionString:"Ain Shams University",institution:{name:"Ain Shams University",country:{name:"Egypt"}}},{id:"94911",title:"Dr.",name:"Boulenouar",middleName:null,surname:"Mesraoua",slug:"boulenouar-mesraoua",fullName:"Boulenouar Mesraoua",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94911/images/system/94911.png",biography:"Dr Boulenouar Mesraoua is the Associate Professor of Clinical Neurology at Weill Cornell Medical College-Qatar and a Consultant Neurologist at Hamad Medical Corporation at the Neuroscience Department; He graduated as a Medical Doctor from the University of Oran, Algeria; he then moved to Belgium, the City of Liege, for a Residency in Internal Medicine and Neurology at Liege University; after getting the Belgian Board of Neurology (with high marks), he went to the National Hospital for Nervous Diseases, Queen Square, London, United Kingdom for a fellowship in Clinical Neurophysiology, under Pr Willison ; Dr Mesraoua had also further training in Epilepsy and Continuous EEG Monitoring for two years (from 2001-2003) in the Neurophysiology department of Zurich University, Switzerland, under late Pr Hans Gregor Wieser ,an internationally known epileptologist expert. \n\nDr B. Mesraoua is the Director of the Neurology Fellowship Program at the Neurology Section and an active member of the newly created Comprehensive Epilepsy Program at Hamad General Hospital, Doha, Qatar; he is also Assistant Director of the Residency Program at the Qatar Medical School. \nDr B. Mesraoua's main interests are Epilepsy, Multiple Sclerosis, and Clinical Neurology; He is the Chairman and the Organizer of the well known Qatar Epilepsy Symposium, he is running yearly for the past 14 years and which is considered a landmark in the Gulf region; He has also started last year , together with other epileptologists from Qatar, the region and elsewhere, a yearly International Epilepsy School Course, which was attended by many neurologists from the Area.\n\nInternationally, Dr Mesraoua is an active and elected member of the Commission on Eastern Mediterranean Region (EMR ) , a regional branch of the International League Against Epilepsy (ILAE), where he represents the Middle East and North Africa(MENA ) and where he holds the position of chief of the Epilepsy Epidemiology Section; Dr Mesraoua is a member of the American Academy of Neurology, the Europeen Academy of Neurology and the American Epilepsy Society.\n\nDr Mesraoua's main objectives are to encourage frequent gathering of the epileptologists/neurologists from the MENA region and the rest of the world, promote Epilepsy Teaching in the MENA Region, and encourage multicenter studies involving neurologists and epileptologists in the MENA region, particularly epilepsy epidemiological studies. \n\nDr. Mesraoua is the recipient of two research Grants, as the Lead Principal Investigator (750.000 USD and 250.000 USD) from the Qatar National Research Fund (QNRF) and the Hamad Hospital Internal Research Grant (IRGC), on the following topics : “Continuous EEG Monitoring in the ICU “ and on “Alpha-lactoalbumin , proof of concept in the treatment of epilepsy” .Dr Mesraoua is a reviewer for the journal \"seizures\" (Europeen Epilepsy Journal ) as well as dove journals ; Dr Mesraoua is the author and co-author of many peer reviewed publications and four book chapters in the field of Epilepsy and Clinical Neurology",institutionString:"Weill Cornell Medical College in Qatar",institution:{name:"Weill Cornell Medical College in Qatar",country:{name:"Qatar"}}},{id:"282429",title:"Prof.",name:"Covanis",middleName:null,surname:"Athanasios",slug:"covanis-athanasios",fullName:"Covanis Athanasios",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/282429/images/system/282429.jpg",biography:null,institutionString:"Neurology-Neurophysiology Department of the Children Hospital Agia Sophia",institution:null},{id:"190980",title:"Prof.",name:"Marwa",middleName:null,surname:"Mahmoud Saleh",slug:"marwa-mahmoud-saleh",fullName:"Marwa Mahmoud Saleh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/190980/images/system/190980.jpg",biography:"Professor Marwa Mahmoud Saleh is a doctor of medicine and currently works in the unit of Phoniatrics, Department of Otolaryngology, Ain Shams University in Cairo, Egypt. She got her doctoral degree in 1991 and her doctoral thesis was accomplished in the University of Iowa, United States. Her publications covered a multitude of topics as videokymography, cochlear implants, stuttering, and dysphagia. She has lectured Egyptian phonology for many years. Her recent research interest is joint attention in autism.",institutionString:"Ain Shams University",institution:{name:"Ain Shams University",country:{name:"Egypt"}}},{id:"259190",title:"Dr.",name:"Syed Ali Raza",middleName:null,surname:"Naqvi",slug:"syed-ali-raza-naqvi",fullName:"Syed Ali Raza Naqvi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259190/images/system/259190.png",biography:"Dr. Naqvi is a radioanalytical chemist and is working as an associate professor of analytical chemistry in the Department of Chemistry, Government College University, Faisalabad, Pakistan. Advance separation techniques, nuclear analytical techniques and radiopharmaceutical analysis are the main courses that he is teaching to graduate and post-graduate students. In the research area, he is focusing on the development of organic- and biomolecule-based radiopharmaceuticals for diagnosis and therapy of infectious and cancerous diseases. Under the supervision of Dr. Naqvi, three students have completed their Ph.D. degrees and 41 students have completed their MS degrees. He has completed three research projects and is currently working on 2 projects entitled “Radiolabeling of fluoroquinolone derivatives for the diagnosis of deep-seated bacterial infections” and “Radiolabeled minigastrin peptides for diagnosis and therapy of NETs”. He has published about 100 research articles in international reputed journals and 7 book chapters. 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From 1985 to 2004, he served as a Full Professor of Biochemistry at the Universidad Nacional de La Plata. He is a member of the National Research Council (CONICET), Argentina, and the Argentine Society for Biochemistry and Molecular Biology (SAIB). His laboratory has been interested for many years in the lipid peroxidation of biological membranes from various tissues and different species. Dr. Catalá has directed twelve doctoral theses, published more than 100 papers in peer-reviewed journals, several chapters in books, and edited twelve books. He received awards at the 40th International Conference Biochemistry of Lipids 1999 in Dijon, France. He is the winner of the Bimbo Pan-American Nutrition, Food Science and Technology Award 2006 and 2012, South America, Human Nutrition, Professional Category. In 2006, he won the Bernardo Houssay award in pharmacology, in recognition of his meritorious works of research. 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In many cases, these diseases have adapted so well that they have developed efficient resilience methods in the human host and can live in the host for years. Others, particularly some blood parasites, can cause very acute diseases and are responsible for millions of deaths yearly. Many parasitic diseases are classified as neglected tropical diseases because they have received minimal funding over recent years and, in many cases, are under-reported despite the critical role they play in morbidity and mortality among human and animal hosts. The current topic, Parasitic Infectious Diseases, in the Infectious Diseases Series aims to publish studies on the systematics, epidemiology, molecular biology, genomics, pathogenesis, genetics, and clinical significance of parasitic diseases from blood borne to intestinal parasites as well as zoonotic parasites. We hope to cover all aspects of parasitic diseases to provide current and relevant research data on these very important diseases. In the current atmosphere of the Coronavirus pandemic, communities around the world, particularly those in different underdeveloped areas, are faced with the growing challenges of the high burden of parasitic diseases. At the same time, they are faced with the Covid-19 pandemic leading to what some authors have called potential syndemics that might worsen the outcome of such infections. 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